Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors

ABSTRACT

Novel compounds are provided which are 11-beta-hydroxysteroid dehydrogenase type I inhibitors. 11-beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 11-beta-hydroxysteroid dehydrogenase type I inhibitor therapy. These novel compounds of formula I: 
                         
or stereoisomers or pharmaceutically acceptable salts thereof, wherein G, Q, X, Y, R 3 , R 3a , and R 3b  are defined herein.

CROSS-REFERENCES TO RELATED APPLICATION

This application claims priority benefit under Title 35 §119(e) of U.S.provisional Application 60/976,506, filed Oct. 1, 2007, the contents ofwhich are herein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

The steroid hormone cortisol is a key regulator of many physiologicalprocesses. However, an excess of cortisol, as occurs in Cushing'sDisease, provokes severe metabolic abnormalities including: type 2diabetes, cardiovascular disease, obesity, and osteoporosis. Manypatients with these diseases, however, do not show significant increasesin plasma cortisol levels. In addition to plasma cortisol, individualtissues can regulate their glucocorticoid tone via the in situconversion of inactive cortisone to the active hormone cortisol. Indeed,the normally high plasma concentration of cortisone provides a readysupply of precursor for conversion to cortisol via the intracellularenzyme 11-beta-hydroxysteroid dehydrogenase type I (11beta-HSD1).

11beta-HSD1 is a member of the short chain dehydrogenase superfamily ofenzymes. By catalyzing the conversion of cortisone to cortisol,11beta-HSD1 controls the intracellular glucocorticoid tone according toits expression and activity levels. In this manner, 11beta-HSD1 candetermine the overall metabolic status of the organ. 11beta-HSD1 isexpressed at high levels in the liver and at lower levels in manymetabolically active tissues including the adipose, the CNS, thepancreas, and the pituitary. Taking the example of the liver, it ispredicted that high levels of 11beta-HSD1 activity will stimulategluconeogenesis and overall glucose output. Conversely, reduction of11beta-HSD1 activity will down regulate gluconeogenesis resulting inlower plasma glucose levels.

Various studies have been conducted that support this hypothesis. Forexample, transgenic mice expressing 2× the normal level of 11beta-HSD1in only the adipose tissue show abdominal obesity, hyperglycemia, andinsulin resistance. (Masuzaki, H. et al., “A Transgenic Model ofVisceral Obesity and the Metabolic Syndrome”, Science, 294:2166-2170(2001). Conversely, when the 11beta-HSD1 gene is ablated by homologousrecombination, the resulting mice are resistant to diet induced obesityand the accompanying dysregulation of glucose metabolism (Morton, N. M.et al., “Novel Adipose Tissue-Mediated Resistance to Diet-inducedVisceral Obesity in 11β-Hydroxysteroid Dehydrogenase Type 1-DeficientMice”, Diabetes, 53:931-938 (2004). In addition, treatment of geneticmouse models of obesity and diabetes (ob/ob, db/db and KKAy mice) with aspecific inhibitor of 11beta-HSD1 causes a decrease in glucose outputfrom the liver and an overall increase in insulin sensitivity (Alberts,P. et al., “Selective Inhibition of 11β-Hydroxysteroid DehydrogenaseType I Improves Hepatic Insuling Sensitivity in Hyperglycemic MiceStrains”, Endocrinology, 144:4755-4762 (2003)). Furthermore, inhibitorsof 11beta-HSD1 have been shown to be effective in treating metabolicsyndrome and atherosclerosis in high fat fed mice (Hermanowski-Vosatkaet al., J. Exp. Med., 202(4):517-527 (2002)). Based in part on thesestudies, it is believed that local control of cortisol levels isimportant in metabolic diseases in these model systems. In addition, theresults of these studies also suggest that inhibition of 11beta-HSD1will be a viable strategy for treating metabolic diseases such as type 2diabetes, obesity, and the metabolic syndrome.

Lending further support to this idea are the results of a series ofpreliminary clinical studies. For example, several reports have shownthat adipose tissue from obese individuals has elevated levels of11beta-HSD1 activity. In addition, studies with carbenoxolone, a naturalproduct derived from licorice that inhibits both 11beta-HSD1 and11beta-HSD2 (converts cortisol to cortisone in kidney) have shownpromising results. A seven day, double blind, placebo controlled, crossover study with carbenoxolone in mildly overweight individuals with type2 diabetes showed that patients treated with the inhibitor, but not theplacebo group, displayed a decrease in hepatic glucose production(Andrews, R. C. et al., J. Clin. Endocrinol. Metab., 88:285-291 (2003)).This observation is consistent with the inhibition of 11beta-HSD1 in theliver. The results of these preclinical and early clinical studiesstrongly support the concept that treatment with a potent and selectiveinhibitor of 11beta-HSD1 will be an efficacious therapy in patientsafflicted with type 2 diabetes, obesity, and the metabolic syndrome.

SUMMARY OF THE INVENTION

In accordance with the present invention, bicyclic and related compoundsare provided that have the general structure of formula I:

wherein G, Q, X, Y, R₃, R_(3a), and R_(3b) are defined below.

The compounds of the present invention inhibit the activity of theenzyme 11-beta-hydroxysteroid dehydrogenase type I. Consequently, thecompounds of the present invention may be used in the treatment ofmultiple diseases or disorders associated with 11-beta-hydroxysteroiddehydrogenase type I, such as diabetes and related conditions,microvascular complications associated with diabetes, the macrovascularcomplications associated with diabetes, cardiovascular diseases,Metabolic Syndrome and its component conditions, inflammatory diseasesand other maladies. Examples of diseases or disorders associated withthe activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type Ithat can be prevented, inhibited, or treated according to the presentinvention include, but are not limited to, diabetes, hyperglycemia,impaired glucose tolerance, insulin resistance, hyperinsulinemia,retinopathy, neuropathy, nephropathy, delayed wound healing,atherosclerosis and its sequelae (acute coronary syndrome, myocardialinfarction, angina pectoris, peripheral vascular disease, intermittentclaudication), abnormal heart function, myocardial ischemia, stroke,Metabolic Syndrome, hypertension, obesity, dislipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL,non-cardiac ischemia, infection, cancer, vascular restenosis,pancreatitis, neurodegenerative disease, lipid disorders, cognitiveimpairment and dementia, bone disease, HIV protease associatedlipodystrophy, glaucoma and inflammatory diseases, such as, rheumatoidarthritis, Cushing's Disease, Alzheimer's Disease and osteoarthritis.

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds, and for methods ofusing such compounds. In particular, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound of formula I alone or in combination with apharmaceutically acceptable carrier.

Further, in accordance with the present invention, a method is providedfor preventing, inhibiting, or treating the progression or onset ofdiseases or disorders associated with the activity of the enzyme11-beta-hydroxysteroid dehydrogenase type I, such as defined above andhereinafter, wherein a therapeutically effective amount of a compound offormula I is administered to a mammalian, i.e., human, patient in needof treatment.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Further, the present invention provides a method for preventing,inhibiting, or treating the diseases as defined above and hereinafter,wherein a therapeutically effective amount of a combination of acompound of formula I and another compound of formula I and/or at leastone other type of therapeutic agent, is administered to a mammalian,i.e., human, patient in need of treatment.

Further, the present invention provides for crystalline forms of thecompounds of formula I, pharmaceutical compositions employing suchcrystalline forms, and for methods of using such forms.

Furthermore, the present invention provides for processes for preparingcompounds of formula I. These processes may be characterized, withoutlimitation, by a) facile adaptation to larger scale production, such aspilot plant or manufacturing scales; b) process steps and/or techniquesenabling improvements in the purity (including chiral purity), stabilityand/or ease of handling of intermediates and/or final compounds; and/orc) fewer process steps.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows observed (experimental at room temperature) and simulated(calculated at room temperature) powder x-ray diffraction patterns (CuKαλ=1.5418 Å) of an N-1 crystalline form of a salt of a compound ofFormula I.

FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of theN-1 crystalline form of a salt of a compound of Formula I.

FIG. 3 shows a thermogravimetric analysis (TGA) curve of the N-1crystalline form of a salt of a compound of Formula I.

FIG. 4 shows a moisture sorption isotherm analysis of the N-1crystalline form of a salt of a compound of Formula I.

FIG. 5 shows observed (experimental at room temperature) and simulated(calculated at room temperature) powder x-ray diffraction patterns (CuKαλ=1.5418 Å) of an N-2 crystalline form of a salt of a compound ofFormula I.

FIG. 6 shows a differential scanning calorimetry (DSC) thermogram of theN-2 crystalline form of a salt of a compound of Formula I.

FIG. 7 shows a thermogravimetric analysis (TGA) curve of the N-2crystalline form of a salt of a compound of Formula I.

FIG. 8 shows observed (experimental at room temperature) and simulated(calculated at room temperature) powder x-ray diffraction patterns (CuKαλ=1.5418 Å) of another N-1 crystalline form of a salt of a compound ofFormula I.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds of formula I

enantiomers, diastereomers, or salts thereof wherein:

Q is L, L_(aa) or L_(ee);

X is C and Y is N; or

X is N and Y is C;

G is R₄, R_(4aa) or R_(4ee);

L is -alkenyl-(W₁)_(n), -cycloalkyl-(W₁)_(n) or -alkyl-(W₂)_(n);

L_(aa) is -alkenyl-(W₁)_(n) or -alkyl-(W_(2aa))_(n);

L_(ee) is -alkenyl-(W_(1ee))_(n), -cycloalkyl-(W₁)_(n) or-alkyl-(W_(2ee))_(n);

n is 1 to 3;

W₁, at each occurrence, is independently halogen, —OH, —CN, —CO₂R₆,—CONR₈R_(8a), —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SOR₆, —SO₂R₆,—NR₉SO₂R_(9a), —NR₉CO₂R_(9a), —NR₉COR_(9a), alkyl, cycloalkyl,haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio,arylsulfonyl, alkylamino, amino, aminoalkyl, arylamino orheteroarylamino;

W_(1ee) is independently halogen, —OH, —CN, —CO₂R₆, —CONR₈R_(8a),—OCONR₈R_(8a), —SO₂NR₈R_(8a), —SOR₆, —SO₂R₆, —NR₉SO₂R_(9a),—NR₉CO₂R_(9a), —NR₉COR_(9a), cycloalkyl, alkyl, haloalkyl, alkoxy,aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino,amino, aminoalkyl, arylamino or heteroarylamino;

W₂ is independently halogen, —OH, —CO₂H, —CN, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), —NR₉CO₂R_(9a), —NR₉COR_(9a), cycloalkyl, alkyl,haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino, amino oraminoalkyl;

W_(2aa) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), —NR₉CO₂R_(9a), —NR₉COR_(9a), —OR_(9b)OR_(9b)Si(R_(9b))₃,cycloalkyl, alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio,alkylamino, amino or aminoalkyl;

W_(2ee) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), —NR₉CO₂R_(9a), —NR₉COR_(9a), cycloalkyl, alkyl,haloalkyl, alkenyl, haloalkoxy, alkylthio, amino, aminoalkyl, aryl,heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);provided that W_(2aa)or W_(2ee) are not only halogen or alkyl;

R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, —CO₂R_(8a), —CONR₈R_(8a), —SO₂NR₈R_(8a), —SOR_(8a), —SO₂R_(8a),—NR₈SO₂R₆, —NR₈CO₂R₆, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy,alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino,aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl orheterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may beoptionally substituted with R₇, R_(7a), R_(7b), and R_(7c);

R₄ is alkyl, cycloalkyl or heterocyclyl, all of which may be optionallysubstituted with one or more substituents selected from halogen, —OH,—OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,—OCONR₈R_(8a), —CONR₈R_(8a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl,amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c);

R_(4aa) is cycloalkyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN,—NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₈R_(8a), —CONR₈R_(8a),—NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl orheteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);

R_(4ee) is alkyl or cycloalkyl, both of which may be optionallysubstituted with one or more substituents selected from halogen, —OH,—OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,—OCONR₈R_(8a), —CONR₈R_(8a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl,amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c);

R₅, at each occurrence, is independently hydrogen, alkyl, cycloalkyl,aryl, haloalkyl, COR_(8a), CO₂R_(8a), SO₂NR₈R_(8a), or SO₂R_(8a);

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl, all of which may be optionally substituted with R₇, R_(7a),R_(7b), and R_(7c);

R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are independentlyhalo, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, aryl, aryloxy,arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, —CO₂R₈, —CONR₈R_(8a), hydroxyalkyl,acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy,aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido,alkanoylamino, arylcarbonylamino, alkylsilicaalkyloxy, —SO₂R_(9b)—NO₂,—CN or thiol, wherein the aryl or heteroaryl may be optionallysubstituted with R₁₀, R_(10a), R_(10b), and R_(10c);

R₈ and R_(8a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl, all of which may beoptionally substituted with R₁₀, R_(10a), R_(10b), and R_(10c);

or alternatively R₈ and R_(8a) can be taken together with the nitrogento which they are attached to form a heterocyclyl ring containing 1, 2,3, or 4 heteroatoms independently selected from the group consisting ofN, NH, O and S, which may be optionally substituted with R₁₀, R_(10a),R_(10b), and R_(10c);

R₉ and R_(9a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl, arylalkyl, heteroaryl or heterocyclyl, all of whichmay be optionally substituted with R₁₀, R_(10a), R_(10b), and R_(10c);

R_(9b), at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl, all of which may be optionally substituted with R₁₀,R_(10a), R_(10b), and R_(10c); and

R₁₀, R_(10a), R_(10b), and R_(10c), at each occurrence, areindependently halo, alkyl, haloalkyl, cyanoalkyl, alkoxy, aryl, aryloxy,arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —NO₂, —CN or thiol;

provided that:

(a) W₁, W_(1ee), W₂, or W_(2aa) is not cycloalkyl when n is 1 and R₄,R_(4aa)or R_(4ee) are cycloalkyl;

(b) W_(2ee) is not cycloalkyl, aryl, heteroaryl or heterocyclyl when nis 1 and R_(4ee) is cycloalkyl;

(c) R₇, R_(7a), R_(7b), and R_(7c) must be substituted with at least oneR₁₀, R_(10a), R_(10b), or R_(10c) when (i) L_(ee) is cycloalkyl, (ii)R_(4ee) is cycloalkyl substituted with aryl, heterocyclyl or heteroaryl,(iii) the aryl, heteroaryl or heterocyclyl is substituted with R₇,R_(7a), R_(7b), or R_(7c); and (iv) R₇, R_(7a), R_(7b), and R_(7c) isaryl, heteroaryl or heterocyclyl;

(d) L_(aa) and L_(ee) are not C₁₋₃alkyl or haloC₁₋₃alkyl when R_(4aa)orR_(4ee) are substituted with an optionally substituted aryl moiety; and

(e) W_(2ee) is not halogen, alkyl, haloalkyl or aryl when R_(4ee) isalkyl.

In another embodiment, compounds are those in which the compound is acompound of formula Iaa, Idd or Iee:

provided that:

(a) W₁, W_(1ee), W₂, or W_(2aa) is not cycloalkyl when n is 1 and R₄,R_(4aa)or R_(4ee) are cycloalkyl;

(b) W_(2ee) is not cycloalkyl, aryl, heteroaryl or heterocyclyl when nis 1 and R_(4ee) is cycloalkyl;

(c) R₇, R_(7a), R_(7b), and R_(7c) must be substituted with at least oneR₁₀, R_(10a), R_(10b), or R_(10c) when (i) L_(ee) is cycloalkyl, (ii)R_(4ee) is cycloalkyl substituted with aryl, heterocyclyl or heteroaryl,(iii) the aryl, heteroaryl or heterocyclyl is substituted with R₇,R_(7a), R_(7b), or R_(7c); and (iv) R₇, R_(7a), R_(7b), and R_(7c) isaryl, heteroaryl or heterocyclyl;

(d) L_(aa) and L_(ee) are not C₁₋₃alkyl or haloC₁₋₃alkyl when R_(4aa) orR_(4ee) are substituted with an optionally substituted aryl moiety; and

(e) W_(2ee) is not halogen, alkyl, haloalkyl or aryl when R_(4ee) isalkyl.

In another embodiment, compounds are those in which:

L is -alkenyl-(W₁)_(n) or -alkyl-(W₂)_(n);

L_(aa) is -alkenyl-(W₁)_(n) or -alkyl-(W_(2aa))_(n);

L_(ee) is -alkenyl-(W_(1ee))_(n), -cycloalkyl-(W₁)_(n) or-alkyl-(W_(2ee))_(n);

n is 1 to 3;

W₁, at each occurrence, is independently halogen, —OH, —CN, —CO₂R₆,—CONR₈R_(8a), —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SOR₆, —SO₂R₆,—NR₉SO₂R_(9a), —NR₉CO₂R_(9a), alkyl, cycloalkyl, haloalkyl, alkoxy,aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino,aminoalkyl, arylamino or heteroarylamino;

W_(1ee) is independently halogen, —OH, —CN, —CO₂R₆, —CONR₈R_(8a),—OCONR₈R_(8a), —SO₂NR₈R_(8a), —SOR₆, —SO₂R₆, —NR₉SO₂R_(9a),—NR₉CO₂R_(9a), cycloalkyl, alkyl, haloalkyl, alkoxy, aryloxy,haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl,arylamino or heteroarylamino;

W₂ is independently halogen, —OH, —CO₂H, —CN, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), —NR₉CO₂R_(9a), —NR₉COR_(9a), cycloalkyl, alkyl,haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylamino, amino oraminoalkyl;

W_(2aa) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), —NR₉CO₂R_(9a), —NR₉COR_(9a), —OR_(9b)OR_(9b)Si(R_(9b))₃,cycloalkyl, alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio,alkylamino, amino or aminoalkyl;

W_(2ee) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), —NR₉CO₂R_(9a), —NR₉COR_(9a), cycloalkyl, alkyl,haloalkyl, alkenyl, haloalkoxy, alkylthio, aminoalkyl, aryl, heteroarylor heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may beoptionally substituted with R₇, R_(7a), R_(7b), and R_(7c); providedthat W_(2aa)or W_(2ee) are not only halogen;

R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, —CO₂R_(8a), —CONR₈R_(8a), —SO₂NR₈R_(8a), —SOR_(8a), —SO₂R_(8a),—NR₈SO₂R₆, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl,haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl,arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, whereinthe aryl, heteroaryl or heterocyclyl may be optionally substituted withR₇, R_(7a), R_(7b), and R_(7c);

R₄ is alkyl or cycloalkyl, both of which may be optionally substitutedwith one or more substituents selected from halogen, —OH, —OR₆, —SR₆,—OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₈R_(8a),—CONR₈R_(8a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino,heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroarylor heterocyclyl may be optionally substituted with R₇, R_(7a), R_(7b),and R_(7c);

R_(4aa) is cycloalkyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN,—NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₈R_(8a), —CONR₈R_(8a),—SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, whereinthe alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionallysubstituted with R₇, R_(7a), R_(7b), and R_(7c);

R_(4ee) is alkyl or cycloalkyl, both of which may be optionallysubstituted with one or more substituents selected from halogen, —OH,—OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,—OCONR₈R_(8a), —CONR₈R_(8a), —SO₂R₆, alkyl, alkoxy, aryl, amino,heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroarylor heterocyclyl may be optionally substituted with R₇, R_(7a), R_(7b),and R_(7c);

R₅, at each occurrence, is independently hydrogen, alkyl, cycloalkyl,aryl, haloalkyl, COR_(8a) or CO₂R_(8a);

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl, all of which may be optionally substituted with R₇, R_(7a),R_(7b), and R_(7c);

R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are independentlyhalo, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, aryl, aryloxy,arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, —CO₂R₈, —CONR₈R_(8a), hydroxyalkyl,acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy,aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido,alkanoylamino, arylcarbonylamino, —SO₂R_(9b)—NO₂, —CN or thiol, whereinthe aryl or heteroaryl may be optionally substituted with R₁₀, R_(10a),R_(10b), and R_(10c);

R₈ and R_(8a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl, all of which may beoptionally substituted with R₁₀, R_(10a), R_(10b), and R_(10c);

or alternatively R₈ and R_(8a) can be taken together with the nitrogento which they are attached to form a heterocyclyl ring containing 1, 2,3, or 4 heteroatoms independently selected from the group consisting ofN, NH, O and S, which may be optionally substituted with R₁₀, R_(10a),R_(10b), and R_(10c);

R₉ and R_(9a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl, arylalkyl, heteroaryl or heterocyclyl, all of whichmay be optionally substituted with R₁₀, R_(10a), R_(10b), and R_(10c);

R_(9b), at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl, all of which may be optionally substituted with R₁₀,R_(10a), R_(10b), and R_(10c);

R₁₀, R_(10a), R_(10b), and R_(10c), at each occurrence, areindependently halo, alkyl, haloalkyl, cyanoalkyl, alkoxy, aryl, aryloxy,arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —NO₂, —CN or thiol;

provided that:

(a) W₁, W_(1ee), W₂, or W_(2aa) is not cycloalkyl when n is 1 and R₄,R_(4aa)or R_(4ee) are cycloalkyl;

(b) W_(2ee) is not cycloalkyl, aryl, heteroaryl or heterocyclyl when nis 1 and R_(4ee) is cycloalkyl;

(c) R₇, R_(7a), R_(7b), and R_(7c) must be substituted with at least oneR₁₀, R_(10a), R_(10b), or R_(10c) when (i) L_(ee) is cycloalkyl, (ii)R_(4ee) is cycloalkyl substituted with aryl, heterocyclyl or heteroaryl,(iii) the aryl, heteroaryl or heterocyclyl is substituted with R₇,R_(7a), R_(7b), or R_(7c); and (iv) R₇, R_(7a), R_(7b), and R_(7c) isaryl, heteroaryl or heterocyclyl;

(d) L_(aa) and L_(ee) are not C₁₋₃alkyl or haloC₁₋₃alkyl when R_(4aa) orR_(4ee) are substituted with an optionally substituted aryl moiety; and

(e) W_(2ee) is not halogen, alkyl, haloalkyl or aryl when R_(4ee) isalkyl.

In another embodiment, compounds are those in which:

L is -alkenyl-(W₁)_(n) or -alkyl-(W₂)_(n);

L_(aa) is -alkenyl-(W₁)_(n) or -alkyl-(W_(2aa))_(n);

L_(ee) is -alkenyl-(W_(1ee))_(n), -cycloalkyl-(W₁)_(n) or-alkyl-(W_(2ee))_(n);

n is 1 to 3;

W₁, at each occurrence, is independently halogen, —OH, —CN, —CO₂R₆,—CONR₈R_(8a), —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SOR₆, —SO₂R₆,—NR₉SO₂R_(9a), alkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio,arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino orheteroarylamino;

W_(1ee) is independently halogen, —OH, —CN, —CO₂R₆, —CONR₈R_(8a),—OCONR₈R_(8a), —SO₂NR₈R_(8a), —SOR₆, —SO₂R₆, —NR₉SO₂R_(9a), alkyl,haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio,arylsulfonyl, alkylamino, aminoalkyl, arylamino or heteroarylamino;

W₂ is independently halogen, —OH, —CO₂H, —CN, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), —NR₉COR_(9a), alkyl, haloalkyl, alkoxy, alkenyl,haloalkoxy, alkylthio, alkylamino, amino or aminoalkyl;

W_(2aa) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), —NR₉COR_(9a), —OR_(9b)OR_(9b)Si(R_(9b))₃, alkyl, alkoxy,alkenyl, haloalkoxy, alkylthio, alkylamino, amino or aminoalkyl;

W_(2ee) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), —NR₉CO₂R_(9a), alkyl, alkenyl, haloalkoxy, alkylthio oraminoalkyl;

provided that W_(2aa)or W_(2ee) are not only halogen;

R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, —CO₂R_(8a), —CONR₈R_(8a), —SO₂NR₈R_(8a), —SOR_(8a), —SO₂R_(8a),alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio,arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino,heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c);

R₄ is alkyl or cycloalkyl, both of which may be optionally substitutedwith one or more substituents selected from halogen, —OH, —OR₆, —SR₆,—OCOR₆, —CN, —COR₆, —CO₂R₆, —CO₂H, —OCONR₈R_(8a), —CONR₈R_(8a), —SO₂R₆,alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein thealkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionallysubstituted with R₇, R_(7a), R_(7b), and R_(7c);

R_(4aa) is cycloalkyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN,—COR₆, —CO₂R₆, —CO₂H, —OCONR₈R_(8a), —CONR₈R_(8a), —SO₂R₆, alkyl,alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substitutedwith R₇, R_(7a), R_(7b), and R_(7c);

R_(4ee) is alkyl, which may be optionally substituted with one or moresubstituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN, —COR₆,—CO₂R₆, —CO₂H, —OCONR₈R_(8a), —CONR₈R_(8a), —SO₂R₆, alkyl, alkoxy, aryl,amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c);

R₆, at each occurrence, is independently alkyl, cycloalkyl, aiyl orheteroaryl, all of which may be optionally substituted with R₇, R_(7a),R_(7b), and R_(7c);

R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are independentlyhalo, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, aryl, aryloxy,arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, —CO₂R₈, —CONR₈R_(8a), hydroxyalkyl,acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy,aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido,alkanoylamino, arylcarbonylamino, —SO₂R_(9b)—NO₂, —CN or thiol, whereinthe aryl or heteroaryl may be optionally substituted with R₁₀, R_(10a),R_(10b), and R_(10c);

R₈ and R_(8a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl, all of which may beoptionally substituted with R₁₀, R_(10a), R_(10b), and R_(10c);

or alternatively R₈ and R_(8a) can be taken together with the nitrogento which they are attached to form a heterocyclyl ring containing 1, 2,3, or 4 heteroatoms independently selected from the group consisting ofN, NH, O and S, which may be optionally substituted with R₁₀, R_(10a),R_(10b), and R_(10c);

R₉ and R_(9a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl, arylalkyl, heteroaryl or heterocyclyl, all of whichmay be optionally substituted with R₁₀, R_(10a), R_(10b), and R_(10c);

R_(9b), at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl, all of which may be optionally substituted with R₁₀,R_(10a), R_(10b), and R_(10c); and

R₁₀, R_(10a), R_(10b), and R_(10c), at each occurrence, areindependently halo, alkyl, haloalkyl, cyanoalkyl, alkoxy, aryl, aryloxy,arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —NO₂, —CN or thiol.

In another embodiment, compounds are those in which:

L is -alkenyl-(W₁)_(n) or -alkyl-(W₂)_(n);

L_(aa) is -alkenyl-(W₁)_(n) or -alkyl-(W_(2aa))_(n);

L_(ee) is -cycloalkyl-(W₁)_(n) or -alkyl-(W_(2ee))_(n);

n is 1 to 3;

W₁, at each occurrence, is independently halogen, —OH, —CN, —CO₂R₆,—CONR₈R_(8a), —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SOR₆, —SO₂R₆,—NR₉SO₂R_(9a), alkyl, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio,arylthio, arylsulfonyl, aminoalkyl, arylamino or heteroarylamino;

W₂ is independently halogen, —OH, —CO₂H, —CN, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), —NR₉COR_(9a), alkyl, haloalkyl, alkoxy, alkenyl,haloalkoxy, alkylthio, alkylamino or aminoalkyl;

W_(2aa) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), —NR₉COR_(9a), —OR_(9b)OR_(9b)Si(R_(9b))₃, alkyl, alkoxy,alkenyl, haloalkoxy, alkylthio, alkylamino or aminoalkyl;

W_(2ee) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), alkyl, alkenyl, haloalkoxy, alkylthio or aminoalkyl;

provided that W_(2aa)or W_(2ee) are not only halogen;

R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, —CO₂R_(8a), —CONR₈R_(8a), —SO₂NR₈R_(8a), alkyl, haloalkyl,cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio,arylsulfonyl, alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl,heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);

R₄ is alkyl or cycloalkyl, both of which may be optionally substitutedwith one or more substituents selected from halogen, —OH, —OR₆, —SR₆,—OCOR₆, —CN, —COR₆, —CO₂R₆, —CO₂H, —OCONR₈R_(8a), —CONR₈R_(8a), —SO₂R₆,alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein thealkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionallysubstituted with R₇, R_(7a), R_(7b), and R_(7c);

R_(4aa) is cycloalkyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN,—COR₆, —CO₂R₆, —CO₂H, —OCONR₈R_(8a), —CONR₈R_(8a), —SO₂R₆, alkyl,alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substitutedwith R₇, R_(7a), R_(7b), and R_(7c);

R_(4ee) is alkyl, which may be optionally substituted with one or moresubstituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN, —COR₆,—CO₂R₆, —CO₂H, —OCONR₈R_(8a), —CONR₈R_(8a), —SO₂R₆, alkyl, alkoxy, aryl,amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c);

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl, all of which may be optionally substituted with R₇, R_(7a),R_(7b), and R_(7c);

R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are independentlyhalo, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, —CO₂R₈, —CONR₈R_(8a), hydroxyalkyl,acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy,aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido,alkanoylamino, arylcarbonylamino, —SO₂R_(9b)—NO₂, —CN or thiol, whereinthe aryl or heteroaryl may be optionally substituted with R₁₀, R_(10a),R_(10b), and R_(10c);

R₈ and R_(8a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl, all of which may beoptionally substituted with R₁₀, R_(10a), R_(10b), and R_(10c);

R₉ and R_(9a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl, arylalkyl, heteroaryl or heterocyclyl, all of whichmay be optionally substituted with R₁₀, R_(10a), R_(10b), and R_(10c);

R_(9b), at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl, all of which may be optionally substituted with R₁₀,R_(10a), R_(10b), and R_(10c); and

R₁₀, R_(10a), R_(10b), and R_(10c), at each occurrence, areindependently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —NO₂, —CN or thiol.

In yet another embodiment, compounds are those in which:

L is -alkyl-(W₂)_(n);

L_(aa) is -alkenyl-(W₁)_(n) or -alkyl-(W_(2aa))_(n);

L_(ee) is -cycloalkyl-(W₁)_(n) or -alkyl-(W_(2ee))_(n);

n is 1 to 2;

W₁, at each occurrence, is independently halogen, —OH, —CN, —CO₂R₆,—CONR₈R_(8a), —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SOR₆, —SO₂R₆, alkyl,haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio,arylsulfonyl, aminoalkyl, arylamino or heteroarylamino;

W₂ is independently halogen, —OH, —CO₂H, —CN, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —SO₂NR₉R_(9a), —SO-alkyl, —SO₂-alkyl, —NR₉SO₂R_(9a),—NR₉COR_(9a), alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio,alkylamino or aminoalkyl;

W_(2aa) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), alkyl, alkoxy, alkenyl, haloalkoxy, alkylthio, alkylaminoor aminoalkyl;

W_(2ee) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₉R_(9a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), alkyl, alkenyl, haloalkoxy, alkylthio or aminoalkyl;

provided that W_(2aa)or W_(2ee) are not only halogen;

R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, —CO₂R_(8a), alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy,haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl,arylamino, heteroarylamino, aryl, heteroaryl or heterocyclyl, whereinthe aryl, heteroaryl or heterocyclyl may be optionally substituted withR₇, R_(7a), R_(7b), and R_(7c);

R₄ is alkyl or cycloalkyl, both of which may be optionally substitutedwith one or more substituents selected from halogen, —OH, —OR₆, —SR₆,—CN, —COR₆, —CO₂R₆, —CO₂H, —CONR₈R_(8a), —SO₂R₆, alkyl, alkoxy, aryl,amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c);

R_(4aa) is cycloalkyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —SR₆, —CN, —COR₆,—CO₂R₆, —CO₂H, —CONR₈R_(8a), —SO₂R₆, alkyl, alkoxy, aryl, amino,heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroarylor heterocyclyl may be optionally substituted with R₇, R_(7a), R_(7b),and R_(7c);

R_(4ee) is alkyl, which may be optionally substituted with one or moresubstituents selected from halogen, —OH, —OR₆, —SR₆, —CN, —COR₆, —CO₂R₆,—CO₂H, —CONR₈R_(8a), —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl orheteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl, all of which may be optionally substituted with R₇, R_(7a),R_(7b), and R_(7c);

R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are independentlyhalo, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, —CO₂R₈, —CONR₈R_(8a), hydroxyalkyl,acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy,aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido,alkanoylamino, arylcarbonylamino, —SO₂R_(9b) —NO₂, —CN or thiol, whereinthe aryl or heteroaryl may be optionally substituted with R₁₀, R_(10a),R_(10b), and R_(10c);

R₈ and R_(8a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl or heteroaryl, all of which may be optionallysubstituted with R₁₀, R_(10a), R_(10b), and R_(10c);

R₉ and R_(9a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl, arylalkyl or heteroaryl, all of which may beoptionally substituted with R₁₀, R_(10a), R_(10b), and R_(10c);

R_(9b), at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl, all of which may be optionally substituted with R₁₀,R_(10a), R_(10b), and R_(10c); and

R₁₀, R_(10a), R_(10b), and R_(10c), at each occurrence, areindependently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —NO₂, —CN or thiol.

In another embodiment, compounds are those in which:

L is -alkyl-(W₂)_(n);

L_(aa) is -alkenyl-(W₁)_(n) or -alkyl-(W_(2aa))_(n);

L_(ee) is -cycloalkyl-(W₁)_(n) or -alkyl-(W_(2ee))_(n);

n is 1 to 2;

W₁, at each occurrence, is independently halogen, —OH, —CN, —CO₂R₆,—CONR₈R_(8a), —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SOR₆, —SO₂R₆, alkyl,haloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio,arylsulfonyl, arylamino or heteroarylamino;

W₂ is independently halogen, —OH, —CO₂H, —CN, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), alkyl, haloalkyl, alkoxy, alkenyl, haloalkoxy, alkylthio,alkylamino or aminoalkyl;

W_(2aa) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), alkyl, alkoxy, alkenyl, haloalkoxy or alkylthio;

W_(2ee) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), alkyl, alkenyl, haloalkoxy or alkylthio;

provided that W_(2aa)or W_(2ee) are not only halogen;

R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy,alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino,heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c);

R₄ is cycloalkyl, which may be optionally substituted with one or moresubstituents selected from halogen, —OH, —OR₆, —SR₆, —CN, —COR₆, —CO₂R₆,—CO₂H, —CONR₈R_(8a), —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl orheteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);

R_(4aa) is cycloalkyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —SR₆, —CN, —COR₆,—CO₂R₆, —CO₂H, —CONR₈R_(8a), —SO₂R₆, alkyl, alkoxy, aryl, amino,heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroarylor heterocyclyl may be optionally substituted with R₇, R_(7a), R_(7b),and R_(7c);

R_(4ee) is alkyl, which may be optionally substituted with one or moresubstituents selected from halogen, —OH, —OR₆, —SR₆, —CN, —COR₆, —CO₂R₆,—CO₂H, —CONR₈R_(8a), —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl orheteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl, all of which may be optionally substituted with R₇, R_(7a),R_(7b), and R_(7c);

R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are independentlyhalo, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, —CO₂R₈, —CONR₈R_(8a), hydroxyalkyl,acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy,aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido,alkanoylamino, arylcarbonylamino, —SO₂R_(9b)—NO₂, —CN or thiol, whereinthe aryl or heteroaryl may be optionally substituted with R₁₀, R_(10a),R_(10b), and R_(10c);

R₈ and R_(8a), at each occurrence, is independently hydrogen, alkyl,aryl or heteroaryl, all of which may be optionally substituted with R₁₀,R_(10a), R_(10b), and R_(10c);

R₉ and R_(9a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl or heteroaryl, all of which may be optionallysubstituted with R₁₀, R_(10a), R_(10b), and R_(10c);

R_(9b), at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl, all of which may be optionally substituted with R₁₀,R_(10a), R_(10b), and R_(10c); and

R₁₀, R_(10a), R_(10b), and R_(10c), at each occurrence, areindependently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —NO₂, —CN or thiol.

In still yet another embodiment, compounds are those in which:

L is -alkyl-(W₂)_(n);

L_(aa) is -alkyl-(W_(2aa))_(n);

L_(ee) is -alkyl-(W_(2ee))_(n);

n is 1 to 2;

W₂ is independently halogen, —OH, —CO₂H, —CN, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₉R_(9a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl,—NR₉SO₂R_(9a), alkyl, haloalkyl, alkoxy or haloalkoxy;

W_(2aa) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl, —NR₉SO₂R_(9a),alkyl, alkoxy, alkenyl or haloalkoxy;

W_(2ee) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl, —NR₉SO₂R_(9a),alkyl, alkoxy, alkenyl or haloalkoxy;

provided that W_(2aa)or W_(2ee) are not only halogen;

R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy,alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl,heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);

R₄ is a 3- to 10-membered cycloalkyl, which may be optionallysubstituted with one or more substituents selected from halogen, —OH,—OR₆, —SR₆, —CN, —COR₆, —CO₂R₆, —CO₂H, alkyl, alkoxy, aryl, amino,heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroarylor heterocyclyl may be optionally substituted with R₇, R_(7a), R_(7b),and R_(7c);

R_(4aa) is cycloalkyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —SR₆, —CN, —COR₆,—CO₂R₆, —CO₂H, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl,wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may beoptionally substituted with R₇, R_(7a), R_(7b), and R_(7c);

R_(4ee) is alkyl, which may be optionally substituted with one or moresubstituents selected from halogen, —OH, —OR₆, —SR₆, —CN, —COR₆, —CO₂R₆,—CO₂H, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, whereinthe alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionallysubstituted with R₇, R_(7a), R_(7b), and R_(7c);

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl;

R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are independentlyhalo, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, —CO₂R₈, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —SO₂R_(9b)—NO₂, —CN or thiol, wherein the aryl orheteroaryl may be optionally substituted with R₁₀, R_(10a), R_(10b), andR_(10c);

R₈ and R_(8a), at each occurrence, is independently hydrogen, alkyl oraryl, all of which may be optionally substituted with R₁₀, R_(10a),R_(10b), and R_(10c);

R₉ and R_(9a), at each occurrence, is independently hydrogen, alkyl,cycloalkyl, aryl or heteroaryl, all of which may be optionallysubstituted with R₁₀, R_(10a), R_(10b), and R_(10c);

R_(9b), at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl; and

R₁₀, R_(10a), R_(10b), and R₁₀, at each occurrence, are independentlyhalo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl,arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy,amino, —OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy,heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio,arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —NO₂, —CN or thiol.

In one embodiment, compounds are those in which:

L is -alkyl-(W₂)_(n);

L_(aa) is -alkyl-(W_(2aa))_(n);

L_(ee) is -alkyl-(W_(2ee))_(n);

n is 1 to 2;

W₂ is independently halogen, —OH, —CO₂H, —CN, —CO₂R₆, —CONR₈R_(8a),—OCOR₆, —OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl, alkyl orhaloalkyl;

W_(2aa) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl, —NR₉SO₂R_(9a),alkyl, alkoxy or haloalkoxy;

W_(2ee) is independently halogen, —OH, —CN, —CO₂H, —CO₂R₆, —CONR₈R_(8a),—OCONR₈R_(8a), —SO₂NR₈R_(8a), —SO-alkyl, —SO₂-alkyl, —NR₉SO₂R_(9a),alkyl, alkoxy or haloalkoxy;

provided that W_(2aa) or W_(2ee) are not only halogen;

R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy,alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl,heteroaryl or heterocyclyl;

R₄ is a 3- to 7-membered cycloalkyl, which may be optionally substitutedwith one or more substituents selected from halogen, —OH, —OR₆, —SR₆,—CN, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein thealkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionallysubstituted with R₇, R_(7a), R_(7b), and R_(7c);

R_(4aa) is cycloalkyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —SR₆, —CN, alkyl,alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substitutedwith R₇, R_(7a), R_(7b), and R_(7c);

R_(4ee) is alkyl, which may be optionally substituted with one or moresubstituents selected from halogen, —OH, —OR₆, —SR₆, —CN, —COR₆, —CO₂R₆,—CO₂H, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, whereinthe alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionallysubstituted with R₇, R_(7a), R_(7b), and R_(7c);

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl;

R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are independentlyhalo, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, arylaryl,arylalkyl, cycloalkyl, amino, —OH, —CO₂R₈, hydroxyalkyl, heteroaryl,heteroaryloxy, heteroarylalkyl, alkylthio, arylalkylthio, —NO₂ or —CN,wherein the aryl or heteroaryl may be optionally substituted with R₁₀,R_(10a), R_(10b), and R_(10c);

R₈ and R_(8a), at each occurrence, is independently hydrogen or alkyl,wherein the alkyl may be optionally substituted with R₁₀, R_(10a),R_(10b), and R_(10c); and

R₉ and R_(9a), at each occurrence, is independently hydrogen, alkyl,aryl or heteroaryl, all of which may be optionally substituted with R₁₀,R_(10a), R_(10b), and R_(10c);

R_(9b), at each occurrence, is independently alkyl, aryl or heteroaryl;and

R₁₀, R_(10a), R_(10b), and R_(10c), at each occurrence, areindependently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —NO₂, —CN or thiol.

In still yet another embodiment, compounds are those in which:

L is -alkyl-(W₂)_(n);

L_(aa) is -alkyl-(W_(2aa))_(n);

L_(ee) is -alkyl-(W_(2ee))_(n);

n is 1 to 2;

W₂ is independently halogen, —OH, —CN, —CO₂R₆, —SO-alkyl, —SO₂-alkyl,alkyl, or haloalkyl;

W_(2aa) is independently —OH, —CN, —CO₂R₆, —SO-alkyl, —SO₂-alkyl, alkyl,alkoxy, or haloalkoxy;

W_(2ee) is independently —OH, —CN, —CO₂R₆, —SO-alkyl, —SO₂-alkyl, alkylor haloalkoxy;

R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy,alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl,heteroaryl or heterocyclyl;

R₄ is a 3- or 4-membered cycloalkyl, which may be optionally substitutedwith one or more substituents selected from halogen, —OH, —OR₆, —SR₆,—CN, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein thealkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionallysubstituted with R₇, R_(7a), R_(7b), and R_(7c);

R_(4aa) is cycloalkyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —SR₆, —CN, alkyl,alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substitutedwith R₇, R_(7a), R_(7b), and R_(7c);

R_(4ee) is alkyl, which may be optionally substituted with one or moresubstituents selected from halogen, —OH, —OR₆, —SR₆, —CN, alkyl, alkoxy,aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy,aryl, heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c);

R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl orheteroaryl; and

R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are independentlyhalo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylalkyl, cycloalkyl,amino, —OH, hydroxyalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl,alkylthio, arylalkylthio, —NO₂, or —CN.

In still yet another embodiment, compounds are those in which:

R_(4aa) is cyclopropyl or cyclobutyl, both of which may be optionallysubstituted with one or more substituents selected from halogen, —OH,—OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,—OCONR₈R_(8a), —CONR₈R_(8a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl,amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c); and

R_(4ee) is isopropyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN,—NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₈R_(8a), —CONR₈R_(8a),—NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl orheteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c).

In still yet another embodiment, compounds are those in which thecompound is a compound of formula Iaa or Iee:

In another embodiment, compounds are those compounds in which thecompound is a compound of formula Iaa or Iee:

wherein:

L_(aa) is -alkyl-OH;

L_(ee) is -alkyl-OH;

R₃, R_(3a) and R_(3b) are independently selected from hydrogen, halogen,—CF₃, OCF₃, alkyl or alkoxy.

In another embodiment, compounds are those compounds in which:

R₃, R_(3a) and R_(3b) are independently selected from hydrogen orhalogen;

R_(4aa) is cyclopropyl or cyclobutyl, both of which may be optionallysubstituted with one or more substituents selected from halogen, —OH,—OR₆, —CN, —COR₆, —CO₂R₆, —CO₂H, alkyl, alkoxy, aryl, amino,heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroarylor heterocyclyl may be optionally substituted with R₇, R_(7a), R_(7b),and R_(7c);

R_(4ee) is isopropyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —CN, —COR₆, —CO₂R₆,—CO₂H, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl, whereinthe alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be optionallysubstituted with R₇, R_(7a), R_(7b), and R_(7c);

R₆, at each occurrence, is independently alkyl, or cycloalkyl; and

R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are independentlyhalo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylalkyl, cycloalkyl,amino, —OH, hydroxyalkyl, heteroaryl, heteroaryloxy, alkylthio, —NO₂, or—CN.

In another embodiment, compounds of the present invention are selectedfrom the compounds exemplified in the examples, preferably examples 1,11, 24 and 91, more preferably Example 1.

In another embodiment, a compound of the present invention is thehydrochloride or bisulfate salt of Example 1.

In yet another embodiment, a compound of the present invention is thehydrochloride salt of Example 1.

In still yet another embodiment, the compound of the present inventionis a crystalline form of the hydrochloride salt of Example 1, preferablythe N-1 or N-2 form, more preferably the N-1 form.

In one embodiment, the crystalline form is in substantially pure form.

In one embodiment, the crystalline form of the hydrochloride salt ofExample 1 is characterized by unit cell parameters substantially equalto the following:

Cell Dimensions:

a=13.5209(3)

b=10.0154(2)

c=13.4607(3)

α=90

β=102.139(1)

γ=90

Space group: P2_(i)/c

Molecules/asymmetric unit (Z′): 1

Density, calc g-cm⁻³: 1.358

In one embodiment, the crystalline form of the hydrochloride salt ofExample 1 is characterized by characterized by a powder X-raydiffraction pattern comprising the following 2θ values (Cu Kα λ−1.5418Å) 6.7±0.1, 11.1±0.1, 13.4±0.1, 13.7±0.1, 16.3±0.1, 19.1±0.1, 19.6±0.1,22.3±0.1 and 24.6±0.1 at room temperature.

In one embodiment, the crystalline form of the hydrochloride salt ofExample 1 is characterized by as characterized by a powder X-raydiffraction pattern substantially in accordance with that shown in FIG.1.

In one embodiment, the crystalline form of the hydrochloride salt ofExample 1 is characterized by is characterized by a differentialscanning calorimetry thermogram substantially in accordance with thatshown in FIG. 2, having an endothermic transition above ca. 150° C.

In one embodiment, the crystalline form of the hydrochloride salt ofExample 1 is characterized by a thermal gravimetric analysis curve inaccordance with that shown in FIG. 3, having negligible weight loss upto about 100° C.

In another embodiment, the crystalline form of the hydrochloride salt ofExample 1 is characterized by unit cell parameters substantially equalto the following:

Cell Dimensions:

a=12.908(4)

b=12.813(4)

c=10.959(2)

α=90

β=90

γ=90

Space group: Pca2₁

Molecules/asymmetric unit (Z′): 1

Density, calc g-cm⁻³: 1.335

In another embodiment, the crystalline form of the hydrochloride salt ofExample 1 is characterized by a powder X-ray diffraction patterncomprising the following 2θ values (Cu Kα λ−1.5418 Å) 6.9±0.1, 13.7±0.1,15.4±0.1, 17.4±0.1, 21.2±0.1, 22.4±0.1 and 23.3±0.1 at room temperature.

In another embodiment, the crystalline form of the hydrochloride salt ofExample 1 is characterized by a powder X-ray diffraction patternsubstantially in accordance with that shown in FIG. 5.

In another embodiment, the crystalline form of the hydrochloride salt ofExample 1 is characterized by a differential scanning calorimetrythermogram substantially in accordance with that shown in FIG. 6, havingan endothermic transition above ca. 150° C.

In another embodiment, the crystalline form of the hydrochloride salt ofExample 1 is characterized by a thermal gravimetric analysis curve inaccordance with that shown in FIG. 7, having negligible weight loss upto about 100° C.

In another embodiment, the compound of the present invention is thebisulfate salt of Example 1.

In another embodiment, Example 1 is a crystalline form of the bisulfatesalt, preferably, N-1 form, more preferably a substantially pure form.

In another embodiment, the crystalline form of the bisulfate salt ofExample 1 is characterized by unit cell parameters substantially equalto the following:

Cell Dimensions:

a=10.016(1)

b=19.772(3)

c=10.169(1)

α=90

β=103.454(7)

γ=90

Space group: P2₁/c

Molecules/asymmetric unit (Z′): 1

Density, calc g-cm⁻³: 1.444

In one embodiment, the crystalline form of the bisulfate salt of Example1 is characterized by a powder X-ray diffraction pattern substantiallyin accordance with that shown in FIG. 8.

In another embodiment, the present invention relates to pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound of the present invention, preferably Examples 1, 1G, 1H, 11, 24and 91, alone or, optionally, in combination with a pharmaceuticallyacceptable carrier and/or one or more other agent(s).

In another embodiment, the present invention relates to methods ofinhibiting the activity of the enzyme 11-beta-hydroxysteroiddehydrogenase type I comprising administering to a mammalian patient,for example, a human patient, in need thereof a therapeuticallyeffective amount of a compound of the present invention, preferablyExamples 1, 1G, 1H, 11, 24 and 91, alone, or optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of diseasesor disorders associated with the activity of the enzyme11-beta-hydroxysteroid dehydrogenase type I comprising administering toa mammalian patient, for example, a human patient, in need ofprevention, inhibition, or treatment a therapeutically effective amountof a compound of the present invention, preferably Examples 1, 1G, 1H,11, 24 and 91, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

Examples of diseases or disorders associated with the activity of theenzyme 11-beta-hydroxysteroid dehydrogenase type I that can beprevented, inhibited, or treated according to the present inventioninclude, but are not limited to, diabetes, hyperglycemia, impairedglucose tolerance, insulin resistance, hyperinsulinemia, retinopathy,neuropathy, nephropathy, delayed wound healing, atherosclerosis, acutecoronary syndrome, myocardial infarction, angina pectoris, peripheralvascular disease, intermittent claudication, abnormal heart function,myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity,dislipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia,infection, cancer, vascular restenosis, pancreatitis, neurodegenerativedisease, lipid disorders, cognitive impairment and dementia, bonedisease, HIV protease associated lipodystrophy, glaucoma, rheumatoidarthritis, Cushing's Disease, Alzheimer's Disease and osteoarthritis.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofdiabetes, hyperglycemia, obesity, dislipidemia, hypertension, cognitiveimpairment, rheumatoid arthritis, osteoarthritis, glaucoma, Cushing'sDisease and Metabolic Syndrome comprising administering to a mammalianpatient, for example, a human patient, in need of prevention,inhibition, or treatment a therapeutically effective amount of acompound of the present invention, preferably Examples 1, 1G, 1H, 11, 24and 91, alone, or, optionally, in combination with another compound ofthe present invention and/or at least one other type of therapeuticagent.

In still another embodiment, the present invention relates to a methodfor preventing, inhibiting, or treating the progression or onset ofdiabetes, comprising administering to a mammalian patient, for example,a human patient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a compound of the present invention,preferably Examples 1, 1G, 1H, 11, 24 and 91, alone, or optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In yet still another embodiment, the present invention relates to amethod for preventing, inhibiting, or treating the progression or onsetof hyperglycemia comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, preferably Examples 1, 1G, 1H, 11, 24 and 91, alone,or, optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of obesitycomprising administering to a mammalian patient, for example, a humanpatient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a compound of the present invention,preferably Examples 1, 1G, 1H, 11, 24 and 91, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In one embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofdislipidemia comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, preferably Examples 1, 1G, 1H, 11, 24 and 91, alone,or, optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofhypertension comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, preferably Examples 1, 1G, 1H, 11, 24 and 91, alone,or, optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofcognitive impairment comprising administering to a mammalian patient,for example, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, preferably Examples 1, 1G, 1H, 11, 24 and 91, alone,or, optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofrheumatoid arthritis comprising administering to a mammalian patient,for example, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, preferably Examples 1, 1G, 1H, 11, 24 and 91, alone,or, optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofosteoarthritis comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, preferably Examples 1, 1G, 1H, 11, 24 and 91, alone,or, optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofMetabolic Syndrome comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, preferably Examples 1, 1G, 1H, 11, 24 and 91, alone,or, optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of glaucomacomprising administering to a mammalian patient, for example, a humanpatient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a compound of the present invention,preferably Examples 1, 1G, 1H, 11, 24 and 91, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofCushing's Disease comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, preferably Examples 1, 1G, 1H, 11, 24 and 91, alone,or, optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to pharmaceuticalcompositions comprised of a therapeutically effective amount of acrystalline form of a compound of the present invention, preferablyExamples 1, 1G, 1H, 11, 24 and 91, alone or, optionally, in combinationwith a pharmaceutically acceptable carrier and/or one or more otheragent(s).

In another embodiment, the present invention relates to methods ofinhibiting the activity of the enzyme 11-beta-hydroxysteroiddehydrogenase type I comprising administering to a mammalian patient,for example, a human patient, in need thereof a therapeuticallyeffective amount of a crystalline form of a compound of the presentinvention, preferably Examples 1, 1G, 1H, 11, 24 and 91, alone, oroptionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of diseasesor disorders associated with the activity of the enzyme11-beta-hydroxysteroid dehydrogenase type I comprising administering toa mammalian patient, for example, a human patient, in need ofprevention, inhibition, or treatment a therapeutically effective amountof a crystalline form of a compound of the present invention, preferablyExamples 1, 1G, 1H, 11, 24 and 91, alone, or, optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

Examples of diseases or disorders associated with the activity of theenzyme 11-beta-hydroxysteroid dehydrogenase type I that can beprevented, inhibited, or treated according to the present inventioninclude, but are not limited to, diabetes, hyperglycemia, impairedglucose tolerance, insulin resistance, hyperinsulinemia, retinopathy,neuropathy, nephropathy, delayed wound healing, atherosclerosis, acutecoronary syndrome, myocardial infarction, angina pectoris, peripheralvascular disease, intermittent claudication, abnormal heart function,myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity,dislipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia,infection, cancer, vascular restenosis, pancreatitis, neurodegenerativedisease, lipid disorders, cognitive impairment and dementia, bonedisease, HIV protease associated lipodystrophy, glaucoma, rheumatoidarthritis, Cushing's Disease, Alzheimer's Disease and osteoarthritis.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofdiabetes, hyperglycemia, obesity, dislipidemia, hypertension, cognitiveimpairment, rheumatoid arthritis, osteoarthritis, glaucoma, Cushing'sDisease and Metabolic Syndrome comprising administering to a mammalianpatient, for example, a human patient, in need of prevention,inhibition, or treatment a therapeutically effective amount of acrystalline form of a compound of the present invention, preferablyExamples 1, 1G, 1H, 11, 24 and 91, alone, or, optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

In still another embodiment, the present invention relates to a methodfor preventing, inhibiting, or treating the progression or onset ofdiabetes, comprising administering to a mammalian patient, for example,a human patient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a crystalline form of a compound ofthe present invention, preferably Examples 1, 1G, 1H, 11, 24 and 91,alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In yet still another embodiment, the present invention relates to amethod for preventing, inhibiting, or treating the progression or onsetof hyperglycemia comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a crystalline form of acompound of the present invention, preferably Examples 1, 1G, 1H, 11, 24and 91, alone, or, optionally, in combination with another compound ofthe present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of obesitycomprising administering to a mammalian patient, for example, a humanpatient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a crystalline form of a compound ofthe present invention, preferably Examples 1, 1G, 1H, 11, 24 and 91,alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In one embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofdislipidemia comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a crystalline form of acompound of the present invention, preferably Examples 1, 1G, 1H, 11, 24and 91, alone, or, optionally, in combination with another compound ofthe present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofhypertension comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a crystalline form of acompound of the present invention, preferably Examples 1, 1G, 1H, 11, 24and 91, alone, or, optionally, in combination with another compound ofthe present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofcognitive impairment comprising administering to a mammalian patient,for example, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a crystalline form of acompound of the present invention, preferably Examples 1, 1G, 1H, 11, 24and 91, alone, or, optionally, in combination with another compound ofthe present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofrheumatoid arthritis comprising administering to a mammalian patient,for example, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a crystalline form of acompound of the present invention, preferably Examples 1, 1G, 1H, 11, 24and 91, alone, or, optionally, in combination with another compound ofthe present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofosteoarthritis comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a crystalline form of acompound of the present invention, preferably Examples 1, 1G, 1H, 11, 24and 91, alone, or, optionally, in combination with another compound ofthe present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofMetabolic Syndrome comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a crystalline form of acompound of the present invention, preferably Examples 1, 1G, 1H, 11, 24and 91, alone, or, optionally, in combination with another compound ofthe present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of glaucomacomprising administering to a mammalian patient, for example, a humanpatient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a crystalline form of a compound ofthe present invention, preferably Examples 1, 1G, 1H, 11, 24 and 91,alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofCushing's Disease comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a crystalline form of acompound of the present invention, preferably Examples 1, 1G, 1H, 11, 24and 91, alone, or, optionally, in combination with another compound ofthe present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention provides a compound of thepresent invention, preferably Examples 1, 1G, 1H, 11, 24 and 91, for usein therapy for treating a metabolic disease.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention, preferably Examples1, 1G, 1H, 11, 24 and 91, and additional therapeutic agent(s) forsimultaneous, separate or sequential use in therapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention, preferably Examples1, 1G, 1H, 11, 24 and 91, and additional therapeutic agent(s) forsimultaneous, separate or sequential use in treatment of a metabolicdisease.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention, preferably Examples 1, 1G, 1H, 11, 24 and 91; and (c)a package insert stating that the pharmaceutical composition can be usedfor the treatment of a metabolic disease.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising: (d) a second container;wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention, preferably Examples 1, 1G, 1H, 11, 24 and 91; and (c)a package insert stating that the pharmaceutical composition can be usedin combination with a second therapeutic agent to treat a metabolicdisease.

In another embodiment, the present invention provides crystalline formsof compounds of the present invention, preferably Examples 1, 1G, 1H,11, 24 and 91, for use in therapy for treating a metabolic disease.

In another embodiment, the present invention provides combinedpreparations of crystalline forms of compounds of the present invention,preferably Examples 1, 1G, 1H, 11, 24 and 91, and additional therapeuticagent(s) for simultaneous, separate or sequential use in therapy.

In another embodiment, the present invention provides combinedpreparations of crystalline forms of compounds of the present invention,preferably Examples 1, 1G, 1H, 11, 24 and 91, and additional therapeuticagent(s) for simultaneous, separate or sequential use in treatment of ametabolic disease.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a crystalline form ofa compound of the present invention, preferably Examples 1, 1G, 1H, 11,24 and 91; and (c) a package insert stating that the pharmaceuticalcomposition can be used for the treatment of a metabolic disease.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising: (d) a second container;wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a crystalline form ofa compound of the present invention; and (c) a package insert statingthat the pharmaceutical composition can be used in combination with asecond therapeutic agent to treat a metabolic disease.

In another embodiment, a process for preparing a compound having theformula (VII-f) is disclosed

in which said process comprises reacting a hydrazide of formula VII-dwith a carboxylic acid or Ph₃PCl₂/diisopropyl ethylamine in the presenceof a solvent at elevated temperature to afford a 1,2,4-triazolopyridineof formula VII-e and then contacting the 1,2,4-triazolopyridine offormula VII-e with an appropriate acid to provide the compound offormula (VII-f):

In one embodiment, the processes are those in which the hydrazide offormula VII-d is reacted with the carboxylic acid in the presence of asolvent.

In one embodiment, the processes are those in which the hydrazide offormula VII-d is reacted with the carboxylic acid in the presence of asolvent at reflux.

In one embodiment, the processes are those in which the carboxylic acidis selected from acetic acid, p-tosic acid, benzoic acid, 2-,3- or4-chlorobenzoic acid, 4-fluorobenzoic acid, 2-chlorobenzeneacetic acid,2- or 4-methylbenzoic acid, 4-methoxybenzoic acid, 2,6-dimethylbenzoicacid, 2,6-dimethoxybenzoic acid, 2-methylpropionic acid and2,2-dimethylpropanoic acid.

In one embodiment, the processes are those in which solvent is selectedfrom toluene, 1-propanol and mixtures thereof, preferably toluene.

In another embodiment, the processes are those in which the hydrazide offormula VII-d

is prepared by reacting a hydrazinylpyridinyl hydrochloride of formulaVII-b with an acid of formula VII-c and oxalyl chloride in a solvent inthe presence of a base:

In one embodiment, the processes are those in which the reaction of thehydrazinylpyridinyl hydrochloride of formula VII-b with an acid offormula VII-c and oxalyl chloride is carried out at ambient temperature.

In one embodiment, the processes are those in which the solvent used inthe reaction of the hydrazinylpyridinyl hydrochloride of formula VII-bwith an acid of formula VII-c and oxalyl chloride is selected fromtoluene, N,N-dimethylformamide, diethylamine, tetrahydrofuran, water,dichloromethane, 2-methyl THF, methyl tert-butyl ether and mixturesthereof, preferably, N,N-dimethylformamide, tetrahydrofuran and mixturesthereof.

In one embodiment, the processes are those in which the base used in thereaction of the hydrazinylpyridinyl hydrochloride of formula VII-b withan acid of formula VII-c and oxalyl chloride is selected from sodiumhydroxide, potassium carbonate, triethylamine and dipotassium phosphate,preferably sodium hydroxide and potassium carbonate, more preferably,potassium carbonate.

In another embodiment, the processes are those in which thehydrazinylpyridinyl hydrochloride of formula VII-b

are prepared by first reacting a halopyridine of formula VII-a with ahydrazine at an elevated temperature followed by HCl salt formation withhydrochloric acid to form the hydrazinylpyridinyl hydrochloride offormula VII-b:

In one embodiment, the processes are those in which the halopyridine offormula VII-a is reacted with the hydrazine in an alcohol, preferably,isopropanol, 1-propanol, 1,4-dioxane, dimethoxyethane, and mixturesthereof, or ether.

In one embodiment, the processes are those in which the halopyridine offormula VII-a is reacted with the hydrazine at 90-100° C., preferably,92-94° C.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements of an embodiment may be combined with any andall other elements from any of the embodiments to describe additionalembodiments.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

One enantiomer of a compound of Formula I may display superior activitycompared with the other. Thus, all of the stereochemistries areconsidered to be a part of the present invention. When required,separation of the racemic material can be achieved by HPLC using achiral column or by a resolution using a resolving agent such ascamphonic chloride as in Young, S. D. et al., Antimicrobial Agents andChemotherapy, 2602-2605 (1995).

To the extent that compounds of the formula I, and salts thereof, mayexist in their tautomeric form, all such tautomeric forms arecontemplated herein as part of the present invention.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom or ring is replaced with a selectionfrom the indicated group, provided that the designated atom's or ringatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substituent is keto (i.e., ═O), then 2hydrogens on the atom are replaced.

When any variable (e.g., R₄) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with (R₄)_(m) and m is0-3, then said group may optionally be substituted with up to three R₄groups and R₄ at each occurrence is selected independently from thedefinition of R_(4.) Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups containing 1 to 20carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, inthe normal chain, such as methyl, ethyl, propyl, isopropyl, butyl,t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl,octyl, 2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, thevarious branched chain isomers thereof, and the like as well as suchgroups may optionally include 1 to 4 substituents such as halo, forexample F, Br, Cl, or I, or CF₃, alkyl, alkoxy, aryl, aryloxy,aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl,heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy,aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido,alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl,trihaloalkyl, and/or alkylthio.

Unless otherwise indicated, the term “alkenyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons, and morepreferably 1 to 8 carbons in the normal chain, which include one to sixdouble bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl,2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl,4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may beoptionally substituted with 1 to 4 substituents, namely, halogen,haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido,arylcarbonyl-amino, nitro, cyano, thiol, alkylthio, and/or any of thealkyl substituents set out herein.

Unless otherwise indicated, the term “alkynyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons and morepreferably 2 to 8 carbons in the normal chain, which include one triplebond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl,4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl,4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl,and the like, and which may be optionally substituted with 1 to 4substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl,cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino,nitro, cyano, thiol, and/or alkylthio, and/or any of the alkylsubstituents set out herein.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 10 rings, preferably 1 to 3 rings, including monocyclicalkyl, bicyclic alkyl (or bicycloalkyl) and tricyclic alkyl, containinga total of 3 to 20 carbons forming the ring, preferably 3 to 15 carbons,more preferably 3 to 10 carbons, forming the ring and which may be fusedto 1 or 2 aromatic rings as described for aryl, which includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol, and/or alkylthio, and/orany of the substituents for alkyl.

Where alkyl groups as defined above have single bonds for attachment toother groups at two different carbon atoms, they are termed “alkylene”groups and may optionally be substituted as defined above for “alkyl”.

Where alkenyl groups as defined above and alkynyl groups as definedabove, respectively, have single bonds for attachment at two differentcarbon atoms, they are termed “alkenylene groups” and “alkynylenegroups”, respectively, and may optionally be substituted as definedabove for “alkenyl” and “alkynyl”.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

Unless otherwise indicated, the term “aryl” as employed herein alone oras part of another group refers to monocyclic and bicyclic aromaticgroups containing 6 to 10 carbons in the ring portion (such as phenyl ornaphthyl, including 1-naphthyl and 2-naphthyl) and may optionallyinclude 1 to 3 additional rings fused to a carbocyclic ring or aheterocyclic ring (such as aryl, cycloalkyl, heteroaryl, orcycloheteroalkyl rings for example

and may be optionally substituted through available carbon atoms with 1,2, or 3 substituents, for example, hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl, or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino,or arylsulfonaminocarbonyl, and/or any of the alkyl substituents set outherein.

Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy”or “aralkoxy” as employed herein alone or as part of another groupincludes any of the above alkyl, aralkyl, or aryl groups linked to anoxygen atom.

Unless otherwise indicated, the term “amino” as employed herein alone oras part of another group refers to amino that may be substituted withone or two substituents, which may be the same or different, such asalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, or thioalkyl. These substituents may befurther substituted with a carboxylic acid and/or any of the R¹ groupsor substituents for R¹ as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl, or hydroxy.

Unless otherwise indicated, the term “lower alkylthio,” “alkylthio,”“arylthio,” or “aralkylthio” as employed herein alone or as part ofanother group includes any of the above alkyl, aralkyl, or aryl groupslinked to a sulfur atom.

Unless otherwise indicated, the term “lower alkylamino,” “alkylamino,”“arylamino,” or “arylalkylamino” as employed herein alone or as part ofanother group includes any of the above alkyl, aryl, or arylalkyl groupslinked to a nitrogen atom.

As used herein, the term “heterocyclyl”, “heterocyclic system” or“heterocyclic ring” is intended to mean a stable 3- to 14-memberedmonocyclic, bicyclic or tricyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom, which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. As used herein, the term “aromatic heterocyclic system” or“heteroaryl” is intended to mean a stable 5- to 7-membered monocyclic orbicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and from 1 to 4 heteroatoms independentlyselected from the group consisting of N, O and S and is aromatic innature.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 1H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, the heterocycles include, but are not limited to, pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl,4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of heteroaryls are 1H-indazole, 2H,6H-1,5,2-dithiazinyl,indolyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyrazolotriazinyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,tetrazolyl, and xanthenyl. In another aspect of the invention, examplesof heteroaryls are indolyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinylisothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyrazolotriazinyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.

The term “heterocyclylalkyl” or “heterocyclyl” as used herein alone oras part of another group refers to heterocyclyl groups as defined abovelinked through a C atom or heteroatom to an alkyl chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein aloneor as part of another group refers to a heteroaryl group as definedabove linked through a C atom or heteroatom to an alkyl chain, alkylene,or alkenylene as defined above.

The term “cyano” as used herein, refers to a —CN group.

The term “nitro” as used herein, refers to an —NO₂ group.

The term “hydroxy” as used herein, refers to an OH group.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,bisulfate and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington 'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,p. 1418 (1985), the disclosure of which is hereby incorporated byreference.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

The term “prodrugs” as employed herein includes esters and carbonatesformed by reacting one or more hydroxyls of compounds of formula I withalkyl, alkoxy, or aryl substituted acylating agents employing proceduresknown to those skilled in the art to generate acetates, pivalates,methylcarbonates, benzoates, and the like.

Various forms of prodrugs are well known in the art and are describedin:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch.31 (Academic Press, 1996);

b) Design of prodrugs, edited by H. Bundgaard (Elsevier, 1985);

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson andH. Bundgaard, eds., Ch. 5, pp. 113-191 (Harwood Academic Publishers,1991); and

d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and JoachimM. Mayer (Wiley-VCH, 2003).

Said references are incorporated herein by reference.

In addition, compounds of the formula I are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% formula Icompound (“substantially pure” compound I), which is then used orformulated as described herein. Such “substantially pure” compounds ofthe formula I are also contemplated herein as part of the presentinvention.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents and/orexhibit polymorphism. Consequently, compounds of formula I can exist inenantiomeric, or diastereomeric forms, or in mixtures thereof. Theprocesses for preparation can utilize racemates, enantiomers, ordiastereomers as starting materials. When diastereomeric or enantiomericproducts are prepared, they can be separated by conventional methods forexample, chromatographic or fractional crystallization. In addition, thecompounds of formula I may exist in tautomeric form. Such tautomericforms of the formula I are also contemplated herein as part of thepresent invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation, handling andstorage to a useful degree of purity from a reaction mixture, andformulation into an efficacious therapeutic agent. The present inventionis intended to embody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to inhibit theactivity of the enzyme 11-beta-hydroxysteroid dehydrogenase type I oreffective to treat or prevent metabolic or other disorders.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

Synthesis

Compounds of the present invention may be prepared as shown in thefollowing reaction schemes and description thereof, as well as relevantliterature procedures that may be used by one skilled in the art.Exemplary reagents and procedures for these reactions appear hereinafterand in the working Examples.

Scheme I describes a method for preparing compounds of formula I-a (asubset of compounds of formula I). A fluoro-, chloro- or bromopyridineintermediate I-b can be obtained commercially, prepared by methods knownin the literature or by other methods known to one skilled in the art.Reaction of a compound of formula I-b with hydrazine was carried out atan elevated temperature to provide an intermediate I-c. Acylation of anintermediate I-c with an acid I-d using an appropriate set of amidecoupling reagents such NMM/isobutylchloformate, EDAC/HOBT or otherreagents described in Bodanszky, M., The Practice of Peptide Synthesis,2nd Ed. (Spring-Verlag, 1993) provides a hydrazide intermediate I-f.Alternatively, a hydrazide I-c can be prepared from the reaction of I-cand an acid chloride I-e in the presence of an appropriate base such asDIEA or TEA. Formation of 1,2,4-triazolopyridine I-g can be achievedfrom the reaction of I-f with Et₃P/CCl₄ in the presence of a base suchas TEA/Hunig's base, or with Ph₃PCl₂ in the presence of a base such asTEA. Formation of 1,2,4-triazolopyridine I-g can also be achieved fromI-f in the presence of acetic acid at an elevated temperature, either bya conventional heating or a microwave reactor. Alternatively, formationof 1,2,4-triazolopyridine I-g can be achieved from the reaction of I-fwith POCl₃ at an elevated temperature or by other methods known to oneskilled in the art. Formation of 1,2,4-triazolopyridine methylcarboxylate I-h can be achieved by palladium catalyzed carbonationreaction in the presence of CO and methanol. The ester I-h can betreated with Grignard reagents or organo lithium reagents to generatecarbinol I-a, or treated with Grignard reagent and followed by reductionusing reagent such as NaBH4 to generate hydroxyl compound I-a(R′=hydrogen), or by other methods known to one skilled in the art.

Scheme II describes a method for preparing compounds of formula II-a (asubset of compounds of formula I). Reagents II-b and or II-c can beobtained commercially, prepared by methods known in the literature or byother methods known to one skilled in the art. Formation of a compoundII-a can be obtained via coupling reaction of zinc reagents II-b orboronic acid II-c with a bromo-, chloro- or iodo-substitutedintermediate I-g (Z₁ is Br, Cl or I) in the presence of palladiumcatalyst. The reactions can be carried out at room temperature, or withheating, or done in a microwave reactor.

Scheme III describes a method for preparing compounds of formula III-b,III-c, and III-d (a subset of compounds of formula Iaa). Formation ofcompound III-b can be obtained via coupling reaction of III-a with abromo-, or iodo-substituted intermediate I-g (Z₁ is Br, I) in thepresence of palladium catalyst and a base such as potassium carbonateand zinc fluoride at elevated temperature. The reactions can be carriedout under a conventional procedure or done in a microwave reactor (J.Am. Chem. Soc., 125:11176 (2003)). Alternatively, compound III-b can beprepared by other methods known to one skilled in the art. Acid III-ccan be obtained by hydrolyzing III-b using base such as LiOH. Formationof amide III-d can be achieved by coupling of acid III-c with an amineR′R″NH using an appropriate set of amide coupling reagents suchNMM/isobutylchloformate, EDAC/HOBT or other reagents described inBodanszky, M., The Practice ofPeptide Synthesis, 2nd Ed. (Spring-Verlag,1993). Alternatively, an amide III-d can be prepared from the reactionof a compound of formula III-b and an amine at elevated temperature, orby other methods known to one skilled in the art.

Scheme IV describes a method for preparing compounds of formula IV-b (asubset of compounds of formula Iaa or Iee). Formation of a compound IV-bcan be obtained via metalation (metal-halogen exchange) of I-g by usingalkyl metal reagent such as BuLi or isopropyl magnesium chloride,followed by addition of aldehyde or ketone IV-a to generate IV-b.Alternatively, compound IV-b can be prepared by other methods known toone skilled in the art.

Scheme V describes an alternative method for preparing compounds offormula V-d (a subset of compounds of formula Iaa or Iee). A fluoro-,chloro- or bromopyridine intermediate V-a can be obtained commercially,prepared by methods known in the literature or by other methods known toone skilled in the art. Reaction of a compound of formula V-a withhydrazine in a suitable solvent such as 1-propanol or isopropyl alcoholcan be carried out at an elevated temperature to provide an intermediateV-b. V-b may be isolated directly or via a suitable salt form (e.g., HClsalt). Acylation of an intermediate V-b with an acid I-d using anappropriate set of amide coupling reagents such NMM/isobutylchloformate,EDAC/HOBT or other reagents described in Bodanszky, M., The Practice ofPeptide Synthesis, 2nd Ed. (Spring-Verlag, 1993) provides a hydrazideintermediate V-c. Alternatively, a hydrazide V-c can be prepared fromthe reaction of a compound of formula V-b and an acid chloride I-e(which may be prepared by reaction of acid I-d with oxalyl chloride) inthe presence of a suitable solvent such as toluene, DMF, or THF) in thepresence of an appropriate base such as NaOH, K₂CO₃, DIEA or TEA.Formation of 1,2,4-triazolopyridine II-a can be achieved from thereaction of V-c with Et₃P/CCl₄ in the presence of a base such asTEA/Hunig's base, or Ph₃PCl₂ in the presence of a base such as TEA orDIEA. Formation of 1,2,4-triazolopyridine II-a can also be achieved fromV-c in the presence of a carboxylic acid, such as acetic acid, p-tosicacid, benzoic acid, 2-,3- or 4-chlorobenzoic acid, 4-fluorobenzoic acid,2-chlorobenzeneacetic acid, 2- or 4-methylbenzoic acid, 4-methoxybenzoicacid, 2,6-dimethylbenzoic acid, 2,6-dimethoxybenzoic acid,2-methylpropionic acid and 2,2-dimethylpropanoic acid, in a solvent,such as toluene, at an elevated temperature, such as reflux, eitherunder a conventional procedure or a microwave reactor to afford1,2,4-triazolopyridine V-d. Alternatively, formation of1,2,4-triazolopyridine V-d can be achieved from the reaction of V-c withPOCl₃ at an elevated temperature or by other methods known to oneskilled in the art.

Scheme VI describes a method for preparing compounds of formula VI-e (asubset of compounds of formula Idd). A bromopyridine intermediate VI-acan be obtained commercially, prepared by methods known in theliterature, or by other methods known to one skilled in the art.Treatment of a compound of formula VI-a with n-BuLi or other metallatingreagents followed by addition of a compound VI-b provides a ketoneintermediate VI-c. Formation of a 1,2,3-triazolopyridine VI-d can beachieved by the reaction of a compound VI-c and benzenesulfonohydrazidein the presence of a base such as morpholine (Tetrahedron, 53:8257-8268(1997)), or by other methods known to one skilled in the art followed bycyclization with a reagent such as iodobenzene diacetate. Formation of acompound VI-e can be achieved using similar transformations described inSchemes I to IV, or by other methods known to one skilled in the art.

EXAMPLES

The following working Examples serve to better illustrate, but notlimit, some of the preferred embodiments of the present invention.

General

The term HPLC refers to a Shimadzu high performance liquidchromatography with one of following methods:

Method A: YMC or Phenomenex C18 5 micron 4.6×50 mm column using a 4minute gradient of 0-100% solvent B [90% MeOH: 10% H₂O:0.2% H₃PO₄] and100-0% solvent A [10% MeOH:90% H₂0:0.2% H₃PO₄] with 4 mL/min flow rateand a 1 min. hold, an ultra violet (UV) detector set at 220 nm.

Method B: Phenomenex S5 ODS 4.6×30 mm column, gradient elution 0-100%B/A over 2 min (solvent A=10% MeOH/H₂O containing 0.1% TFA, solventB=90% MeOH/H₂O containing 0.1% TFA), flow rate 5 mL/min, UV detection at220 nm.

Method C: YMC S7 ODS 3.0×50 mm column, gradient elution 0-100% B/A over2 min (solvent A=10% MeOH/H₂O containing 0.1% TFA, solvent B=90%MeOH/H₂O containing 0.1% TFA), flow rate 5 mL/min, UV detection at 220nm.

The term prep HPLC refers to an automated Shimadzu HPLC system using amixture of solvent A (10% MeOH/90%H₂O/0.2%TFA) and solvent B (90%MeOH/10%H₂O/0.2% TFA). The preparative columns were packed with YMC orPhenomenex ODS C18 5 micron resin or equivalent.

Procedure for Characterizing the Crystal Forms

Single Crystal Data

A Bruker SMART 2K CCD diffractometer equipped withgraphite-monochromated Cu Kα radiation, (λ=1.54056 Å) was used tocollect diffraction data at room temperature. A full data set wascollected using the co scan mode over the 20 range with acrystal-to-detector distance of 4.98 cm. An empirical absorptioncorrection utilized the SADABS routine associated with thediffractometer (Bruker AXS. 1998, SMART and SAINTPLUS. Area DetectorControl and Integration Software, Bruker AXS, Madison, Wis., USA). Thefinal unit cell parameters were determined using the entire data set.

All structures were solved by direct methods and refined by thefull-matrix least-squares techniques, using the SHELXTL software package(Sheldrick, G M. 1997, SHELXTL. Structure Determination Programs.Version 5.10, Bruker AXS, Madison, Wis., USA.). The function minimizedin the refinements was Σ_(W)(|F_(O)|−|F_(C)|)². R is defined asΣ∥F_(O)|−|F_(C)∥/Σ|F_(O)| whileR_(W)=[Σ_(W)(|F_(O)|−|F_(C)|)²/Σ_(W)|F_(O)|²]^(1/2), where w is anappropriate weighting function based on errors in the observedintensities. Difference Fourier maps were examined at all stages ofrefinement. All non-hydrogen atoms were refined with anisotropic thermaldisplacement parameters. The hydrogen atoms associated with hydrogenbonding were located in the final difference Fourier maps while thepositions of the other hydrogen atoms were calculated from an idealizedgeometry with standard bond lengths and angles. They were assignedisotropic temperature factors and included in structure factorcalculations with fixed parameters.

Alternatively, single crystal data were collected on a Bruker-Nonius¹CAD4 serial diffractometer. Unit cell parameters were obtained throughleast-squares analysis of the experimental diffractometer settings of 25high-angle reflections. Intensities were measured using Cu Kα radiation(λ=1.5418 Å) at a constant temperature with the θ-2θ variable scantechnique and were corrected only for Lorentz-polarization factors.Background counts were collected at the extremes of the scan for half ofthe time of the scan. Alternately, single crystal data were collected ona Bruker-Nonius Kappa CCD 2000 system using Cu Kα radiation (λ=1.5418Å). Indexing and processing of the measured intensity data were carriedout with the HKL2000 software package² in the Collect program suite.³Alternately, single crystal data were collected on a Bruker-AXS APEX2CCD system using Cu Kα radiation (λ=1.5418 Å). Indexing and processingof the measured intensity data were carried out with the APEX2 softwarepackage/program suite⁴. ¹ BRUKER AXS, Inc., 5465 East Cheryl ParkwayMadison, Wis. 53711 USA² Otwinowski, Z. et al., MacromolecularCrystallography, Academic, NY, publ., Carter, W. C., Jr. et al., eds.,Vol. 276, pp. 307-326 (1997).³ Collect Data collection and processinguser interface: Collect: Data collection software, R. Hooft, Nonius B.V., 1998.⁴APEX2 Data collection and processing user interface: APEX2User Manual, Vol. 27; BRUKER AXS, Inc., 5465 East Cheryl ParkwayMadison, Wis. 53711 USA.

When indicated, crystals were cooled in the cold stream of an Oxfordcryo system⁵ during data collection. ⁵ Oxford Cryosystems Cryostreamcooler: Cosier, J. et al., J. Appl. Cryst., 19:105 (1986).

The structures were solved by direct methods and refined on the basis ofobserved reflections using either the SDP⁶software package with minorlocal modifications or the crystallographic packages MAXUS⁷ or SHELXTL⁴.⁶SDP, Structure Determination Package, Enraf-Nonius, Bohemia N.Y. 11716.Scattering factors, including f′ and f″, in the SDP software were takenfrom the “International Tables for Crystallography” (Kynoch Press,Birmingham, England, 1974), Vol. IV, Tables 2.2A and 2.3.1.⁷MaXussolution and refinement software suite: Mackay, S. et al., maXus: acomputer program for the solution and refinement of crystal structuresfrom diffraction data.

The derived atomic parameters (coordinates and temperature factors) wererefined through full matrix least-squares. The function minimized in therefinements was Σ_(W)(|F_(O)|−|F_(C)|)². R is defined asΣ∥F_(O)|−|F_(C)∥/Σ|F_(O)| whileR_(W)=[Σ_(W)(|F_(O)|−|F_(C)|)²/Σ_(W)|F_(O)|²]^(1/2), where w is anappropriate weighting function based on errors in the observedintensities. Difference maps were examined at all stages of refinement.Hydrogens were introduced in idealized positions with isotropictemperature factors, but no hydrogen parameters were varied.

PXRD

X-ray powder diffraction (PXRD) data were obtained using a Bruker C2GADDS (General Area Detector Diffraction System). The radiation was CuKα (40 KV, 50 mA). The sample-detector distance was 15 cm. Powdersamples were placed in sealed glass capillaries of 1 mm or less indiameter; the capillary was rotated during data collection. Data werecollected for 3≦2θ≦35° with a sample exposure time of at least 2000seconds. The resulting two-dimensional diffraction arcs were integratedto create a traditional 1-dimensional PXRD pattern with a step size of0.02 degrees 2θ in the range of 3 to 35 degrees 2θ.

Alternatively, X-ray powder diffraction (PXRD) data were obtained usinga Bruker GADDS manual chi platform goniometer. Powder samples wereplaced in thin walled glass capillaries of 1 mm or less in diameter; thecapillary was rotated during data collection. The sample-detectordistance was 17 cm. The radiation was Cu Kα (λ=1.5418 Ang). Data werecollected for 3<2θ<35° with a sample exposure time of at least 300seconds.

DSC

Differential scanning calorimetry (DSC) experiments were performed in aTA Instruments™ model Q2000, Q1000 or 2920. The sample (about 2-6 mg)was weighed in an aluminum pan and recorded accurately to a hundredth ofa milligram, and transferred to the DSC. The instrument was purged withnitrogen gas at 50 mL/min. Data were collected between room temperatureand 300° C. at 10° C./min heating rate. The plot was made with theendothermic peaks pointing down.

TGA

Thermal gravimetric analysis (TGA) experiments were performed in a TAInstruments™ model Q500 or 2950. The sample (about 10-30 mg) was placedin a platinum pan previously tared. The weight of the sample wasmeasured accurately and recorded to a thousandth of a milligram by theinstrument. The furnace was purged with nitrogen gas at 100 mL/min. Datawere collected between room temperature and 300° C. at 10° C./minheating rate.

Moisture Sorption

Moisture sorption isotherms were collected in a VTI SGA-100 SymmetricVapor Analyzer using approximately 10 mg of sample. The sample was driedat 60° C. until the loss rate of 0.0005 wt %/min was obtained for 10minutes. The sample was tested at 25° C. and 3 or 4, 5, 15, 25, 35, 45,50, 65, 75, 85, and 95% RH. Equilibration at each RH was reached whenthe rate of 0.0003 wt %/min for 35 minutes was achieved or a maximum of600 minutes.

ABBREVIATIONS

The following abbreviations are employed in the Examples and elsewhereherein:

-   Ph=phenyl-   Bn=benzyl-   i-Bu=iso-butyl-   Me=methyl-   Et=ethyl-   Pr=propyl-   Bu=butyl-   AIBN=2,2′-Azobisisobutyronitrile-   Aq.=aqueous-   Boc or BOC=tert-butoxycarbonyl-   Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl-   CO=carbon monoxide-   DCM=dichloromethane-   DEAD=Diethyl azodicarboxylate-   DIAD=Diisopropyl azodicarboxylate-   DIEA=N,N-diisopropylethylamine-   DMA=N,N-dimethylacetylamide-   DMF=N,N-dimethylformamide-   DMSO=dimethylsulfoxide-   EtOAc=ethyl acetate-   EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or    1-[(3-(dimethyl)amino)propyl])-3-ethylcarbodiimide hydrochloride)-   FMOC=fluorenylmethoxycarbonyl-   HOAc or AcOH=acetic acid-   HOAT=1-hydroxy-7-azabenzotriazole-   HOBT=1-hydroxybenzotriazole-   IPA=isopropyl alcohol or isopropanol-   LAH=lithium aluminum hydride-   MTBE=methyl tertiary butyl ether-   mCPBA=3-Chloroperoxybenzoic acid-   NMM=N-methyl morpholine-   NBS=N-Bromosuccinimide-   n-BuLi=n-butyllithium-   Oxone®=Monopersulfate-   Pd/C=palladium on carbon-   PtO2=platinum oxide-   PyBOP reagent=benzotriazol-1-yloxy-tripyrrolidino phosphonium    hexafluorophosphate-   RH=relative humidity-   SOCl₂=Thionyl chloride-   TBAF=tetrabutylammonium fluoride-   TBS=tert-Butyldimethylsilyl-   TMS=trimethylsilyl-   TEA=triethylamine-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   Eq. or equiv=equivalent(s)-   min=minute(s)-   h or hr=hour(s)-   L=liter-   mL=milliliter-   pL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=mole(s)-   mmol=millimole(s)-   meq=milliequivalent-   rt or RT=room temperature-   sat or sat'd=saturated-   aq.=aqueous-   TLC=thin layer chromatography-   HPLC=high performance liquid chromatography-   HPLC Rt=HPLC retention time-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS or Mass Spec=mass spectrometry-   NMR=nuclear magnetic resonance-   mp=melting point-   K₃PO₄=potassium phosphate-   Na₂SO₄=sodium sulfate-   SiO₂=silicon dioxide-   EA=ethyl amine-   Et₂O=diethyl ether-   MeOH=methanol-   H₃PO₄=phosphoric acid-   MgSO₄=magnesium sulfate-   Pd(dppf)Cl₂[CH₂Cl₂]=bis(diphenylphosphino)ferrocene]dichloropalladium(II),    complex with dichloromethane (1:1)-   ZnF₂=Zinc Fluoride-   Pd(dba)₂=bis(dibenzylideneacetone)palladium-   P(tBu)₃=tributylphosphine

Example 12-(3-(1-(4-Chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-ol

To a solution of 2-chloro-3-bromopyridine (14.5 g, 75.1 mmol) in 100 mLof dioxane was added anhydrous hydrazine (35.4 mL, 1130 mmol) at RT. Thereaction mixture was heated at reflux for 15 h, and then cooled to RT.After most of the solvent was removed under reduced pressure, theresulting residue was diluted with ethyl acetate, washed with water,dried over Na₂SO₄, and concentrated to provide a residue.Recrystallization of the residue in ethyl acetate and hexanes gavecompound 1A (12.9 g, 91%) as a solid. LC/MS (m/z)=188 (M+H)+.

A stirred solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid(8.71 g, 44.3 mmol) and NMM in THF (200 mL) was cooled 0° C. Once at theprescribed temperature, isobutyl chloroformate was added dropwise over10 min, and the resulting white suspension was stirred for 1h. Afterthis time, a solution of compound 1A (8.33g, 44.3 mmol) in THF (250 mL)was added over 10 min. Upon completion of addition, the reaction mixturewas stirred for 15 min. At the conclusion of this period, the reactionmixture was warmed to RT, where it was stirred for 2 h. After this time,the reaction mixture was partitioned between ethyl acetate and water.The organic phase was separated, dried over Na₂SO₄, and thenconcentrated in vacuo to afford compound 1B (10.2 g, 27.8 mmol, 63%yield) as an off-white solid. LC/MS (m/z)=366 (M+H)+.

A stirred solution of compound 1B (10 g, 27.3 mmol), carbontetrachloride (31.6 mL, 327 mmol) and Hunig's Base (28.6 mL, 164 mmol)in 275 ml of THF was cooled to 0° C. Triethylphosphine (12.1 mL, 82mmol) was added dropwise to the solution over 10 min. Upon completion ofaddition, the reaction mixture was slowly warmed to RT, where it stirredfor 16 h. After this time, the reaction mixture was quenched with H₂ O(100 mL), and extracted ethyl acetate (2×200 mL). The pooled organicphases were washed with brine, dried over Na₂SO₄, and then concentratedin vacuo to afford a yellow solid. The yellow solid was triturated with100 ml of ethyl acetate/Hexane (2:1, v/v), and the resulting mixture wasfiltered. The resulting solid was rinsed with more ethyl acetate (50 ml)and compound 1C (7.2 g) was collected via filtration as a pale-yellowsolid. LC/MS (m/z)=348 (M+H)+.

A pressure reaction flask was charged with compound 1C (2.5 g, 7.17mmol), 1,3-bis(diphenylphosphino)propane (0.592 g, 1.43 mmol),triethylamine (3.00 mL, 21.5 mmol), and MeOH (50 mL). The mixture wasbubbled with CO for 2 min, then sealed and charged with 25 psi of CO(gas). The reaction mixture was heated to 80° C., where it was stirredfor 24 h. After this time, the MeOH was removed in vacuo and 20 ml ofbrine was added. The resulting mixture was extracted with EtOAc (3×30ml). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated to provide the crude product. Thecrude product was purified by column chromatography (eluted withEtOAc/hexane (0 to 100%)) to provide compound 1D (2.02 g) as a lightyellow foam. LC/MS (m/z)=328 (M+H)+.

Example 1

Under a nitrogen atmosphere at RT, a microwave tube was charged with asolution of compound 1D (131 mg, 0.40 mmol) in 3 ml of THF, followed byaddition of methylmagnesium chloride (400 μL, 3 M in THF, 1.2 mmol).Upon completion of addition, the reaction was stirred at RT for 1 h, andthen heated to 65° C. where it stirred for 6 h. After this time, thereaction mixture was cooled to RT. The reaction mixture was quenchedwith brine (3 ml) and extracted with EtOAc (3×5ml). The combined organiclayers were concentrated and purified via column chromatography (40 gsilica gel column, from 0% to 100% EtOAc/Hexane) to provide Example 1(45 mg), as a white foam. LC/MS (m/z)=328 (M+H)+. ¹H NMR (400 MHz,Chloroform-d): δ1.51 (dd,J=6.9, 4.8 Hz, 2H), 1.66 (dd,J=6.8, 4.8 Hz,2H,), 1.74 (s, 6H), 5.12 (s, 1H), 6.70 (t,J=4.0 Hz, 1H), 7.04 (dt, J=12,4.0 Hz, 2H),7.11 (d,J=8.0 Hz, 1H), 7.21 (dt,J=8.0, 4.0 Hz, 2H), 7.21(d,J=7.8, Hz, 1H). ¹³C NMR (100.6 MHz, Chloroform-d₆): δ15.25, 19.83,29.24, 72.04, 113.91, 121.02, 121.17, 127.75, 128.99, 132.73, 137.19,138.37, 148.27, 149.23.

Example 1G2-(3-(1-(4-Chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-olHCl Salt

To a 2.0-liter round-bottomed flask was charged sequentially2-(2-fluoropyridin-3-yl)propan-2-ol (60.0 g, 386.7 mmol., 1.0 equiv.),1-propanol (120 mL) and Na₂CO₃ (43.0 g, 405.7 mmol., 1.05 equiv).Hydrazine monohydrate (96.8 g; 1930 mmol., 5.2 equiv.) was charged tothe flask and the resulting mixture was heated to 92-94° C. Once at theprescribed temperature, the reaction mixture was monitored by HPLC untilthe 2-(2-fluoropyridin-3-yl)propan-2-ol starting material was consumed,which was about 24-26 h. The resulting biphasic slurry was cooled to 20°C. and then water followed by toluene (900 mL) were added. Uponcompletion of addition, the resulting mixture was stirred at 20° C. for˜10-15 minutes. After this time, the organic and aqueous phases wereallowed to settle for 10 min and then the aqueous phase was separated.The organic layer was washed with 20% aqueous brine solution (450 mL)and then concentrated in vacuo at ˜55-60° C. to provide a toluenesolution (˜240 mL). The toluene solution was cooled to 25° C. and1-propanol (60 mL) was added. To the resulting solution was added a 5-6N HCl in IPA solution (0.6 equiv.) during a 30-40 min period. Uponcompletion of addition, a seed of previously prepared2-(2-hydrazinylpyridin-3-yl)propan-2-ol hydrochloride monohydrate (1.0%wt.) and additional 5-6 NHCl in IPA solution (0.7 equiv.) were added.The resulting slurry was stirred at 20° C. for at least 12 hr and thenfiltered. The filter cake was washed with a mixture of 1-propanol andtoluene (9:1, v/v, 200 mL×3) and then dried in vacuo at the roomtemperature for 4-5 hrs. After this time, the filter cake was furtherdried under nitrogen at 40° C. for 2-3 h and then at the roomtemperature for about 16 hours to provide crude compound 1E (52.1 g,60.7% yield, HPLC purity >99% area percent).

Compound 1E was also recrystallized by mixing crude2-(2-hydrazinylpyridin-3-yl)propan-2-ol hydrochloride monohydrate (25 g,113 mmol), IPA (150 mL) and 1-propanol (100.0 mL) in a 500-mLround-bottomed flask. The resulting slurry was warmed under nitrogen to55-60° C. where it stirred for ˜5-10 minutes. After this time, toluene(100 ml) was added. The resulting mixture was seeded with2-(2-hydrazinylpyridin-3-yl)propan-2-ol hydrochloride monohydrate (1.0%wt.) and then additional toluene (100 mL, total toluene, 200 mL) wasadded (total time for complete toluene addition was 30 minutes). Uponcompletion of addition, the mixture was stirred for about 16 hours andthen the resulting slurry was filtered. The filter cake was washed witha toluene and isopropyl alcohol solution (2: 1, v/v, 25 mL×2) and thendried in a vacuum oven at the room temperature under nitrogen sweepingfor about 16 hours to provide recrystallized Compound 1E (13.4 g, 53%recovery, melting point: 88.1-111.2° C. (dec.)). IR (KBr) 3392, 3329,3291, 3246, 3202, 3108, 2983, 1653, 1625, 1600, 1552, 1455, 1390, 1249,1171, 1105, 1050, 963, 940, 878, 798, 788, 765, 690, 502 cm⁻¹. ¹H NMR(400 MHz, DMSO-d₆): δ1.61 (s, 6H), 6.16 (br s, 1H), 6.91 (dd,J=7.3, 5.4Hz, 1H), 7.62 (d,J=7.2 Hz, 1H), 8.03 (d, J=3.9 Hz, 1H), 8.93 (s, 1H),9.65 (br s, 2H). ¹³ C NMR (100.5 MHz, DMSO-d₆): δ30.0, 72.0, 115.8,129.2, 135.2, 141.8, 153.2. HRMS Compound 1E (M+1): calcd 168.1137,found, 168.1137. Anal. Calcd. for Compound 1E: C, 43.35; H, 7.27; N,18.95; Cl, 15.99. Found: C, 43.53; H, 7.29; N, 19.06, Cl, 15.99.

To a slurry of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (34.7 g;177 mmoles; 1.1 equiv.) in toluene (142 mL) was added DMF (124 μL; 1.6mmoles; 0.01 equiv.). Upon completion of addition, the slurry wasstirred at ˜25° C. for ˜5 minutes and then neat oxalyl chloride (14.8mL; 167 mmoles; 1.0 equiv.) was added at room temperature over a 20 min.period. The resulting slurry was stirred for ˜4 hr (the solids graduallydissolved as the reaction proceeded). In a separate flask, a mixture ofcompound 1E (35.5 g; 160 mmoles; 1.0 equiv.) and potassium carbonate (51g; 369 mmoles; 2.3 equiv) in THF (355 mL) was cooled to ˜5° C. Once atthe prescribed temperature, water (248 mL) was added and the biphasicmixture was stirred for 15 min. At the conclusion of this period, theacid chloride solution was transferred to the biphasic solution over a20 minute period. Upon completion of the transfer, the reaction mixturewas stirred for 30 min. The reaction mixture was analyzed by HPLC, whichindicated that the reaction was complete. The aqueous layer was removedand the organic layer was washed with water (180 mL×2) and thenconcentrated via vacuum distillation at ˜60° C. to provide a richproduct solution (178 mL). Toluene (70 mL) was added to the rich productsolution and the resulting solution was heated to ˜70° C. Once at theprescribed temperature, n-heptane (425 mL) was added during a 30 min.period to generate a slurry. The slurry was cooled to ˜20° C. where itstirred for 3 hr. After this time, the slurry was filtered. The filtercake was washed with n-heptane (142 mL) and then dried in vacuo at RTfor 48 hr to provide crude compound 1F (51 g, yield 92%). Crude compound1F was suspended in acetonitrile (770 mL) and water (35 mL), and theresulting mixture was heated to ˜75° C. where it stirred for 5 minutesin order to achieve full dissolution. The resulting solution was thencooled to ˜60° C. Once at the prescribed temperature, water (280 mL) wasadded during a 1 hour period. The resulting slurry was cooled to ˜20° C.during a 2 hr period. Once at the prescribed temperature, the slurry wasstirred for two hours. The resulting solids were collected byfiltration, washed with water (142 mL) and then dried in vacuo at ˜70°C. to afford recrystallized compound 1F (46 g, yield 83%). HPLC purity99.64%.

Compound 1F was also recrystallized by suspending crude compound 1F (17g) in methanol (170 mL) and then heating the resulting slurry to refluxin order to achieve full dissolution. Upon dissolution, water (8.5 mL)was added and the resulting slurry was cooled to ˜20° C. Once at theprescribed temperature, the slurry was stirred for about 16 hours andthen filtered. The filter cake was washed with water (68 mL) and thendried in vacuo at ˜70° C. to provide recrystallized compound 1F (14.1 g,yield 83%, melting point 191° C.). IR (KBr) 3355, 3226, 2978, 1633,1591, 1574, 1541, 1494, 1456, 1384, 1316, 1269, 1240, 1139, 1098, 978,766, 534 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ1.07 (dd,J=6.9, 4.1 Hz, 2H),1.44 (dd,J=6.8, 4.0 Hz, 2H,), 1.51 (s, 6H), 5.72 (s, 1H), 6.69(dd,J=7.4, 4.9 Hz, 1H), 7.39 (dd,J=7.6, 1.5 Hz, 1H), 7.43 (dt,J=5.6, 2.3Hz, 2H), 7.50 (dt, J=5.5, 2.3 Hz, 2H), 7.95 (dd,J=4.9, 1.6 Hz, 1H), 8.97(d,J=3.2 Hz, 1H), 9.06 (dd,J=3.3 Hz, 1H). ¹³C NMR (100.6 MHz, DMSO-d₆):δ14.6, 28.6, 28.8, 71.1, 114.4, 127.0, 128.4, 131.6, 131.8, 132.7,138.7, 145.3, 155.3, 169.7. MS Compound 1F (M+1): m/e, 346.15. Anal.Calcd for Compound 1F: C, 62.52; H, 5.827; N, 12.15; Cl, 10.25. Found:C, 62.58; H, 5.78; N, 12.27, Cl, 10.26.

Example 1G

In a three-necked 50-mL round-bottomed flask, a mixture of compound 1F(1.5 g, 4.34 mmol, 1.0 equiv.), toluene (15 mL) and acetic acid (3 mL,3.2 g, 52.4 mmol, 12.1 equiv.) was heated to ˜100-105° C. where it wasstirred for no less than 35.0 hr. After this time, the mixture wasanalyzed by HPLC, which indicated that the reaction was >97% complete.The reaction mixture was distilled at atmospheric pressure to provide aresidue (˜10.0 mL). Toluene (15 mL) was added to the residue and theresulting mixture was again concentrated with atmospheric distillationto a volume of ˜16.5 mL. The resulting mixture was cooled to 20° C.where it stirred for about 16 hours. At the conclusion of this period,the mixture was diluted with water (12 mL) and then conc. HCl (560 μL,6.5 mmol, 1.5 equiv.) was added. The resulting mixture was stirred for˜10 min and then the organic layer was separated and discarded. Theaqueous layer was extracted with a mixture of toluene/heptane (2:1, v/v,6 mL). The organic layer was again separated and discarded. Toluene (15mL) was added to the aqueous layer and the resulting aqueous biphasicmixture was cooled to ˜5° C. Once at the prescribed temperature, 10NNaOH (aqueous, 950 μL; 9.5 mmoles; 2.2 equiv.) was added to adjust thepH to ˜14. Upon completion of addition, the resulting mixture wasstirred for 15 min and then the organic and aqueous layers wereseparated. The organic layer was washed with 10% wt. NaCl (aqueous, 7.5mL) and then diluted with toluene (7.5 mL). The resulting mixture wasconcentrated by atmospheric distillation to a final volume of ˜13.5 mL.This solution was cooled to ˜20° C. and then a mixture (˜0.5 mL, 0.4equiv.) of conc. HCl (560 μL, aqueous, 6.5 mmoles; 1.5 equiv) in IPA(1.5 mL) was slowly added followed by a seed of Example 1G (7.9 mg,0.5%). To the resulting light slurry was added the remainder (˜1.5 mL,1.1 equiv.) of the conc. HCl/IPA mixture over a 10 minute period. Uponcompletion of addition, the resulting slurry was stirred at ˜20° C. forabout 16 hours. At the conclusion of this period, the slurry wasfiltered. The filter cake was washed with toluene (5 mL) and then driedin vacuo to afford crude Example 1G, HPLC Purity 99.29%, 1.2 g, as awhite solid. Yield=72.8%.

Alternatively, Example 1G can be prepared as follows:

In a 50-mL three necked round bottomed flask, a mixture of compound 1F(1.0 g, 2.95 mmol, 1 equiv.), toluene (5.1 mL) and acetic acid (1.7 mL,1.8 g, 29.5 mmol, 10 equiv.) was heated to ˜100° C. for 24 hr. Themixture was diluted with toluene (15 mL). The resulting mixture wasconcentrated by distillation at ˜110° C. to provide a solution with afinal volume of ˜8.0 mL. This solution was cooled to ˜20° C. and then asolution (˜0.5 mL, 0.5 equiv.) of conc. HCl (540 μL, aqueous, 6.3 mmol.,2.1 equiv.) in isopropyl alcohol (1.5 mL) was added. Upon completion ofaddition, a seed of Example 1G (11.8 mg) was added to generate a lightslurry. To the light slurry was added the remainder (˜1.5 mL, 1.6equiv.) of the conc. HCl/IPA mixture during a 3 minute period. Theresulting slurry was stirred at ˜20° C. for about 16 hours. At theconclusion of this period, the slurry was filtered. The filter cake waswashed with toluene (4 mL) and then dried in vacuo to afford crudeExample 1G, ˜1.0 g, HPLC Purity 99.13%, as a white solid.

Preparation of Crystalline N-1 Form of Example 1G

Crude Example 1G (1.15 g) was dissolved in EtOH (7.5 mL) at ˜65° C. Upondissolution, n-heptane (7.5 mL) and a seed crystal of Example 1G wereadded to generate a seed bed, and the resulting light slurry was stirredfor ˜10 min. After this time, additional n-heptane (15 mL) was addedduring a 15 min. period. This resulting slurry was stirred at 65° C. for30 min and then cooled to ˜20° C. where it stirred for no less than 16hours. At the conclusion of this period, the slurry was filtered. Thefilter cake was washed with 10% ethanol in n-heptanes (5 mL) and thendried in a vacuum oven at 45° C. for about 16 hours to afford Example 1G(1.0 g, yield 63.9%) as a white solid. The material was analyzed by themethods described above to be a crystalline material. The crystallinematerial was assigned the N-1 form. ¹H NMR (600.1 MHz, CD₃OD-d₄): δ1.74(s, 6H), 1.74, 1.82 (overlapped, dd, J=7.6, 5.1 Hz, 2H, 2H), 7.32(d,J=8.6 Hz, 2H), 7.32 (d,J=8.6 Hz, 2H), 7.51 (t,J=7.1 Hz, 1H), 8.02(dd,J=7.3, 0.9 Hz, 1H), 8.51 (dd,J=6.8, 0.9 Hz, 1H). ¹³C NMR (125.8 MHz,CD₃OD-d₄): δ16.1, 20.6, 30.5, 72.6, 119.9, 125.0, 129.6, 130.4, 133.6,134.6, 136.3, 138.3, 144.5, 150.0.

Alternatively, the crystalline N-1 form of Example 1G was prepared fromcrude Example 1G as follows:

Crude Example 1G (˜1.0 g) was dissolved in EtOH (5 mL) at ˜65° C. Upondissolution, n-heptane (5 mL) was added and the resulting mixture wasstirred for ˜10 min. to generate a seed bed. The light slurry wasstirred for ˜10 min and then additional n-heptane (7.5 mL) was addedduring a 15 minute period. Upon completion of addition, the slurry wasstirred for 30 minutes then cooled to ˜20° C. where it stirred for about16 hours. At the conclusion of this period, the slurry was filtered. Thefilter cake was washed with 10% ethanol in n-heptanes (5 mL) and thendried in a vacuum oven at 45° C. for about 16 hours to afford Example 1G(0.8 g, yield 72.4%) as a white solid. HPLC Purity 99.83% area percent.The solid was determined to have similar physical properties asdescribed above.

Preparation of Crystalline N-2 Form of Example 1G

Crude Example 1G (318 mg) was dissolved in toluene (1.8 L) at 90° C. Theresulting solution was stirred at 90° C. for 30 min and then cooledslowly to 20° C. over 3 hours. Once at the prescribed temperature, thecooling bath was turned off and the resulting slurry was stirred forabout 16 hours. After this time, the resulting white solid was collectedby filtration and dried at 30° C. in a vacuum oven for about 16 hours toprovide 220 mg of material. The material was analyzed by PXRD to be acrystalline material. The crystalline material was assigned to be theN-2 form.

Alternatively, the crystalline N-2 form of Example 1G was prepared fromcrude Example 1G as follows:

Crude Example 1G (100 mg) was dissolved in MTBE (0.6 L) at 75° C. Theresulting solution was stirred at 75° C. for 20 minutes and then cooledslowly to 20° C. over 2.5 hours. Once at the prescribed temperature, thecooling bath was turned off and the resulting slurry was stirred forabout 16 hours. After this time, the resulting white solid was collectedby filtration and dried at 30° C. in a vacuum oven for about 16 hours toprovide a solid. The solid was determined to have similar physicalproperties as the N-2 form described above.

The crystalline forms of Example 1G were prepared and are tabulated asExamples 1G(a) and 1G(b) shown in Table 1 below. Said crystalline formscomprise crystals of forms N-1 and N-2. The forms of Example 1G wereanalyzed using one or more of the testing methods described hereinabove.

TABLE 1 Example Form Solvents Type 1G(a) N-1 Butanol Neat crystal 1G(b)N-2 IPA/MeOH/Toluene/MTBE Neat crystal

Example 1G(a)

Single Crystal X-ray Measurements

Following the above Single Crystal Data procedure, the approximate unitcell dimensions in Angstroms (Å), as measured at a sample temperature ofroom temperature, as well as the crystalline cell volume (V), spacegroup (sg), molecules per asymmetric unit, and crystal density for theN-1 form of Example 1G are shown below.

Cell Dimensions:

a=13.5209(3)

b=10.0154(2)

c=13.4607(3)

α=90

β=102.139(1)

γ=90

Space group: P2₁/c

Molecules/asymmetric unit (Z′): 1

Density, calc g-cm⁻³: 1.358

The unit cell parameters were obtained from single crystal X-raycrystallographic analysis according to the procedure described in Stoutet al., X-Ray Structure Determination: A Practical Guide (MacMillian,1968), previously herein incorporated by reference.

A moisture sorption study indicates that the Form N-1 is non-hygroscopicin the range from about 25 to about 75% RH at 25° C. FIG. 4 shows amoisture sorption isotherm analysis of the N-1 crystalline form ofExample 1G.

Powder X-ray Diffraction

X-ray powder diffraction (PXRD) data were obtained using the PXRDprocedure described hereinabove. Table 2a and FIG. 1 show the PXRD datafor the N-1 crystalline form for Example 1G.

TABLE 2a Characteristic diffraction peak positions (degrees 2θ ± 0.1) @RT, based on a high quality pattern collected with a diffractometer(CuKα) with a spinning capillary with 2θ calibrated with a NIST othersuitable standard Peak No. 2-Theta (°) 1 6.7 2 11.1 3 13.4 4 13.7 5 16.36 19.1 7 19.6 8 22.3 9 24.6Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry was conducted for each crystallineform using a TA Instruments™ model Q1000. For each analysis, the DSCcell/sample chamber was purged with 50 mL/min from above of ultra-highpurity nitrogen gas. The instrument was calibrated with high purityindium. The heating rate was 10° C. per minute in the temperature rangebetween 25 and 300° C. The heat flow, which was normalized by sampleweight, was plotted versus the measured sample temperature. The datawere reported in units of watts/gram (“W/g”). The plot was made with theendothermic peaks pointing down. FIG. 2 shows the DSC thermogram for theN-1 crystal form of Example 1G, which was observed to have anendothermic transition above ca. 150° C.

Thermogravimetric Analysis (TGA)

Thermogravimetric analysis was conducted using the procedure describedabove. FIG. 3 shows the TGA curve for the N-1 crystal form of Example1G, which has a negligible weight loss up to about 100° C.

Example 1G(b)

Single Crystal X-ray Measurements

Following the above Single Crystal Data procedure, the approximate unitcell dimensions in Angstroms (Å), as measured at a sample temperature ofroom temperature, as well as the crystalline cell volume (V), spacegroup (sg), molecules per asymmetric unit, and crystal density for theN-2 form of Example 1G are shown below.

Cell Dimensions:

a=12.908(4)

b=12.813(4)

c=10.959(2)

α=90

β=90

γ=90

Space group: Pca2₁

Molecules/asymmetric unit (Z′): 1

Density, calc g-cm⁻³: 1.335

The unit cell parameters were obtained from single crystal X-raycrystallographic analysis according to the procedure described in Stoutet al., X-Ray Structure Determination: A Practical Guide (MacMillian,1968), previously herein incorporated by reference.

Powder X-ray Diffraction

X-ray powder diffraction (PXRD) data were obtained using the PXRDprocedure described hereinabove. Table 2b and FIG. 5 show the PXRD datafor the N-2 crystalline form for Example 1G.

TABLE 2b Characteristic diffraction peak positions (degrees 2θ ± 0.1) @RT, based on a high quality pattern collected with a diffractometer(CuKα) with a spinning capillary with 2θ calibrated with a NIST othersuitable standard Peak No. 2-Theta (°) 1 6.9 2 13.7 3 15.4 4 17.4 5 21.26 22.4 7 23.3Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry was conducted for each crystallineform using a TA Instruments™ model Q1000. For each analysis, the DSCcell/sample chamber was purged with 50 mL/min from above of ultra-highpurity nitrogen gas. The instrument was calibrated with high purityindium. The heating rate was 10C per minute in the temperature rangebetween 25 and 300° C. The heat flow, which was normalized by sampleweight, was plotted versus the measured sample temperature. The datawere reported in units of watts/gram (“W/g”). The plot was made with theendothermic peaks pointing down. FIG. 6 shows the DSC thermogram for theN-2 crystal form of Example 1G, which was observed to have anendothermic transition above ca. 150° C.

Thermogravimetric Analysis (TGA)

Thermogravimetric analysis was conducted using the procedure describedabove. FIG. 7 shows the TGA curve for the N-2 crystal form of Example1G, which has a negligible weight loss up to about 100° C.

Example 1H 2-(3-(1-(4-Chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-ol Bisulfate Salt

In order to affect dissolution, an aqueous sulfuric acid solution (˜5:1v/v) was added to a half-dram vial containing crude Example 1 at roomtemperature. A solid precipitated without agitation within a minute ofthe addition of the aqueous sulfuric acid solution. The resulting solidwas collected by filtration to afford Example 1H as a white solid. Thematerial was analyzed by one or more of the methods described above tobe a crystalline material. The crystalline material was assigned the N-1form.

Single Crystal X-ray Measurements

Following the above Single Crystal Data procedure, the approximate unitcell dimensions in Angstroms (Å), as measured at a sample temperature ofroom temperature, as well as the crystalline cell volume (V), spacegroup (sg), molecules per asymmetric unit, and crystal density for theN-1 form of Example 1H are shown below.

Cell Dimensions:

a=10.016(1)

b=19.772(3)

c=10.169(1)

α=90

β=103.454(7)

γ=90

Space group: P2₁/c

Molecules/asymmetric unit (Z′): 1

Density, calc g-cm⁻³: 1.444

The unit cell parameters were obtained from single crystal X-raycrystallographic analysis according to the procedure described in Stoutet al., X-Ray Structure Determination: A Practical Guide (MacMillian,1968).

Powder X-Ray Diffraction

X-ray powder diffraction (PXRD) data were obtained using the PXRDprocedure described hereinabove. FIG. 8 shows the PXRD data for the N-1crystalline form for Example 1H.

Example 2 1-(3-(1-(4-Chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridine-8-yl)cyclobutanol TFA Salt

To a suspension of 1C (70 mg, 0.2 mmol) in 2 ml of THF at −10° C. wasslowly added iso-propylmagnesium chloride lithium chloride complex(0.602 ml, 0.602 mmol). Upon completion of addition, the mixture wasstirred at −10° C. (briefly warmed to 0° C.) for 1 h, and thencyclobutanone (70.4 mg, 1.0 mmol) was added quickly. The reactionmixture was stirred at −10° C. for 30 min, and then slowly warmed to rtwhere it was stirred for 3 h. After this time, the reaction mixture wasquenched with water and extracted with EtOAc (3×5 ml). The combinedorganic layers were concentrated, and the crude product was purified viaprep-HPLC (H₂O/CH₃CN/TFA, 20% to 100% B, 30×100 Luna column) to obtainExample 2 (15 mg, 16%) as an oil (TFA salt). LC/MS (m/z)=340 (M+H)+.HPLC Purity>95%.

Example 33-(1-(4-Chlorophenyl)cyclopropyl)-8-(prop-1-en-2-yl))-[1,2,4]triazolo[4,3-a]pyridineTFA Salt

Argon was vigorously bubbled through a stirring mixture of compound 1C(0.070 g, 0.201 mmol), boronic ester4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.038 mL,0.201 mmol), and K₃PO₄ (0.107 g, 0.502 mmol) in THF (2 mL) for 5 min.After this time, PdCl₂(dppf)-CH₂Cl₂ (0.016 g, 0.020 mmol) was added.Upon completion of addition, the reaction vessel was flushed with argon,capped, and then heated to 90° C. for 20 h. At the conclusion of thisperiod, the reaction mixture was cooled to rt and filtered to collectthe crude product. The crude compound was purified by prep-HPLC(H₂O/CH₃CN/TFA, 20% to 100% B, 30×100 Luna column) to obtain Example 3(30 mg, 48%) as an oil (TFA salt). LC/MS (m/z)=310 (M+H)+. HPLCPurity>95%.

Example 3B3-(1-(4-Chlorophenyl)cyclopropyl)-8-(prop-1-en-2-yl))-[1,2,4]triazolo[4,3-a]pyridine

To a slurry of compound 1F (15.1 g; 43.6 mmoles; 1 equiv.) in toluene(135 mL) was added phosphoryl chloride (21 mL, 224 mmoles, 5.1 equiv.)over a 5 min period. Upon the completion of addition, the reactionmixture was heated to 95° C. where it was held for 22 hr. After thistime, the reaction mixture was concentrated under vacuum distillation toa volume of ˜45 mL. Acetonitrile (150 mL) was added to the residualsolution. The resulting solution was concentrated by distillation atatmospheric pressure to a minimum volume and then acetonitrile (60 mL)was added to bring the final volume to ˜105 mL. The resulting organicsolution was cooled to ˜5° C. and a solution of potassium carbonate (aq,13.3 g, 95.3 mmoles, 2.2 equiv.) in water (260 mL) was added to providea slurry. The slurry was warmed to ˜20° C. where it stirred for 18 hr.At the conclusion of this period, the slurry was filtered. The filtercake was washed with water (75 mL) and dried in vacuo for ˜3 hr toprovide the crude product (12.1 g).

The crude product was added to a flask followed by toluene (50 mL). Theresulting mixture was stirred for 20 min in order to achieve fulldissolution. Upon full dissolution, a mixture of concentratedhydrochloric acid (4.3 mL, 50.1 mmoles, 1.2 equiv.) and isopropylalcohol (15 mL) was added to the solution over a 15 min period. Theresulting HCl salt slurry was stirred at ˜20° C. for 18 hr. Theresulting solid was collected by filtration, washed with toluene (25mL), and then dried in vacuo for 3 hr to provide Example 3B as the HClsalt (11.2 g). The HCl salt was transferred to a flask and thenacetonitrile (45 mL) and water (45 mL) were added. The resulting mixturewas stirred for ˜5 min in order to achieve full dissolution and thencooled to ˜5° C. Once at the prescribed temperature, a solution ofpotassium carbonate (7 g, 50.1 mmoles, 1.2 equiv.) and water (90 mL) wasadded over a 15 min period. The resulting slurry was stirred for 30 minat room temperature. The resulting solid was collected by filtration,washed with water (60 mL) and then dried in vacuo at room temperaturefor 48 hr to provide Example 3B as the free base (9.5 g). The free base(9.5 g) was dissolved in acetonitrile (45 mL) at ˜40° C. Upon completionof dissolution, the solution was cooled to ˜20° C. and water (90 mL, 6vols) was added. Upon completion of addition, the resulting slurry wasstirred for ˜3 hr. After this time, the resulting solid was collected byfiltration, washed with water (45 mL) and then dried in vacuo at 70° C.for about 18 hours to provide recrystallized Example 3B (yield: 8.5 g,63%. Purity, 99.61%, melting point 128.9° C.). IR (KBr) 3099, 3025,1630, 1601, 1484, 1451, 1368, 1325, 1107, 1091, 1044, 1007, 924, 916,749, 675, 531 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ1.47-1.60 (m, 2H),1.66-1.78 (m, 2H), 2.30 (s, 3H), 5.63 (br s, 1H), 6.75 (t,J=6.9 Hz, 1H),6.78 (s, 1H), 7.18 (s, 1H), 7.16-7.27 (m, 3H), 6.99-7.10 (m, 2H), 7.74(d,J=6.1, 1H). ¹³C NMR (100.6 MHz, CDCl₃): δ15.4, 19.8, 22.0, 113.6,121.0, 121.4, 123.5, 127.6, 128.9, 129.9, 132.6, 137.3, 138.7, 148.4,149.3. Mass C₁₈H₁₇ClN₃ (M+1): m/e, 310.13. Anal. Calcd for C₁₈H₁₆ClN₃:C, 69.79; H, 5.21; N, 13.56; Cl, 11.44. Found: C, 69.44; H, 5.02; N,13.48, Cl, 11.45.

Example 43-(3-(1-(4-Chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridine-8-yl)propan-1-ol

To a solution of zinc chloride (274 mg, 2.0 mmol) in THF (4 mL) wasadded (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide (8.8 mL, 4.4 mmol,0.5M THF) to provide bis(2-(1,3 dioxan-2-yl)ethyl)zinc. In a separatereaction vessel, a mixture of compound 1C (348.6 mg, 1.0 mmol) andpotassium carbonate (276 mg, 2.0 mmol) in DMF (5 mL) was stirred at rtfor 3 h. After this time, argon was bubbled through the mixture for 5minutes and then the bis(2-(1,3 dioxan-2-yl)ethyl)zinc andPd(dppf)Cl₂[CH₂Cl₂] (81.7 mg, 0.10 mmol) were added. Upon completion ofaddition, the reaction vessel was flushed with argon, capped, and thenheated at 90° C. for 16 h. After this time, the reaction mixture waspartitioned between diethyl ether and water and stirred vigorously for15 minutes. The organic phase was separated, dried over Na₂SO₄ andconcentrated in vacuo to yield a residue. The residue was purified viaflash chromatography (SiO₂, 0-100% ethyl acetate/hexanes) followed bypurification via preparative HPLC (Phenomenex Axia Luna column (30×100mm); 0-100% B over 15 min, then 3 min B hold @ 40 mL/min; Solvent A=10%MeCN, 90% H₂O; Solvent B=90% MeCN, 10% H₂O) to afford compound 4A (289mg, 75%) as a pale-yellow foam. LC/MS (m/z)=384 (M+H)+.

To a solution of compound 4A (96.0 mg, 0.25 mmol) in acetone (2.5 mL)was added sulfuric acid (111 μL, 1.0 mmol, 9M). The resulting mixturewas heated to reflux where it was stirred for 2 h. After this time, thereaction mixture was partitioned between ethyl acetate and 50% saturatedaqueous sodium bicarbonate and then solid sodium chloride was addeduntil the aqueous phase was saturated. The organic phase was separated,dried over Na₂SO₄, and concentrated in vacuo to yield a residue. Theresidue was purified via flash chromatography (SiO₂, 0-100% ethylacetate/hexanes) to provide compound 4B (95.6 mg, 73%) as an off-whitefoam.

Example 4

To a 0° C. solution of compound 4B (32.6 mg, 0.1 mmol) in THF (1 mL) wasadded sodium borohydride (3.9 mg, 0.1 mmol) in one portion. Uponcompletion of addition, the reaction mixture was stirred for 1 h. Afterthis time, a 50% saturated aqueous ammonium chloride (1 mL) was addedand the resulting mixture was stirred vigorously for 1 h. At theconclusion of this period, ethyl acetate (2 mL) was added, and theorganic layer was separated, dried over Na₂SO₄, and then concentrated invacuo to yield a residue. The residue was purified via preparative HPLC(Phenomenex Axia Luna column (30×100 mm); 0-100% B over 15 min, then 3min B hold @ 40 mL/min; Solvent A=10% MeCN, 90% H₂ O with 0.1% TFA;Solvent B=90% MeCN, 10% H₂O with 0.1% TFA), and the desired fractionswere collected, washed with saturated aqueous NaHCO₃ and thenconcentrated to afford Example 4 (9.5 mg, 29%) as a pale-yellow foam.LC/MS (m/z)=328 (M+H)+. HPLC Purity>95%.

Example 5 Methyl2-(3-(1-(4-chlorophenyl)cyclobutyl)-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-2-methylpropanoate

To a crimp-top microwave vial was added8-bromo-3-(1-(4-chlorophenyl)cyclobutyl)-[1,2,4]triazolo[4,3-a]pyridine(50 mg, 0.14 mmol) (prepared in a manner similar to Example 1), ZnF₂(7.2 mg, 0.069 mmol), and Pd(dba)₂ (7.9 mg, 0.014 mmol). The vial wasflushed with argon, and then P(tBu)₃ (28 μL, 1.0 M, 0.028 mmol),(1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (36 mg, 0.207 mmol),and DMF (1mL) were added. The vial was capped and heated at 80° C. for16 h. After this time, the reaction mixture was cooled to roomtemperature and partitioned between ethyl acetate/Et₂O (1:1) and water.The organic phase was separated, dried over Na₂SO₄, and concentrated invacuo to yield a residue. The residue was purified by prep HPLC(Phenomenex Axia Luna column (30×100 mm); 50-70% B over 15 min, then 3min B hold @ 40 mL/min; Solvent A=10% MeOH, 90% H₂O, 0.1% TFA; SolventB=90% MeOH, 10% H₂O, 0.1% TFA). The fractions containing product wereneutralized via passage (gravity) through a bicarbonate cartridge(PolymerLabs, PL-HCO₃ MP-Resin, 0.36 mmol, one cartridge per 18mL tube)and then concentrated to provide Example 5 (16 mg, 30%) as a white foam.LC/MS (m/z)=384 (M+H)+. HPLC Purity>95%.

Example 6

To a dry 250 mL round bottom flask was added 15 mL of THF and 2.5 Mn-BuLi (8.4 mL, 21.1 mmol). The flask was cooled to −78° C. and to itwas added a solution of 2,6-dibromopyridine (5 g, 21.1 mmol) in 40 mL ofTHF, dropwise via addition funnel, under nitrogen atmosphere. Uponcompletion of addition, the mixture was stirred for an additional 15 minat −78° C. To the resulting dark green solution at −78° C. was added1-(4-chlorophenyl)cyclopropanecarbonitrile (4.5 g, 25.3 mmol) over 1min. The reaction mixture was then allowed to warm to room temperatureand to it was added 6N HCl (27.5 mL, 165 mmol) and the reaction mixturewas heated to reflux for 10 min, followed by stirring at roomtemperature for 1.5 h. The solution was then made basic by addition of1N NaOH at 0° C. The organic layer was separated and the aqueous layerwas extracted with EtOAc (3×50 mL). The combined organic layers weredried (MgSO₄) and concentrated in vacuo to yield 8.7 g of crude materialas an orange oil, which was purified by flash chromatography over 330 gof silica gel (eluted with Hexanes:EtOAc 95:5) to give compound 6A (3.3g, 47% yield) as a white solid. ¹H NMR: δ 7.62 (d,J=8 Hz, 1H), 7.47(t,J=8 Hz, 1H), 7.37 (d,J=8 Hz, 1H), 7.24 (d,J=8 Hz, 2H), 7.13 (d,J=8Hz, 2H), 1.79-1.76 (m, 2H), 1.30-1.28 (m, 2H). LC/MS (m/z)=338 (M+H)⁺.

To a 25 mL round bottom flask was added compound 6A (0.12 g, 0.36 mmol),p-toluenesulfonhydrazide (0.07 g, 0.36 mmol) and 0.7 mL of methanol. Thereaction mixture was stirred at 65° C. for 6 h, cooled to roomtemperature, and the solid was isolated by vacuum filtration to affordcompound 6B (0. 13 g, 71% yield) as a white powder. ¹H NMR: δ 13.34 (s,1H), 7.90 (d,J=8 Hz, 2H), 7.51-7.50 (m, 2H), 7.42-7.40 (m, 1H), 7.31(d,J=8 Hz, 2H), 7.08 (d,J=9 Hz, 2H), 6.90 (d,J=9, 2H), 2.43 (s, 3H),1.36 (dd,J=2, 7 Hz, 2H), 1.22 (dd,J=2, 7, 2H). LC/MS (m/z)=506 (M+H)⁺.

To a solution of compound 6B (0.68 g, 1.3 mmol) in 13 mL ofdichloromethane was added iodobenzene diacetate (0.65 g, 2.0 mmol) atroom temperature. The reaction mixture was stirred at room temperaturefor 45 min. After this time, the solvent was removed in vacuo, 3 mL ofmethanol was added and the resulting solid was isolated by vacuumfiltration to yield compound 6C (125 mg, 27% yield) as an off-whitesolid. ¹H NMR: δ 7.28 (s, 4H), 7.16 (dd,J=1, 7 Hz, 1H), 7.05 (dd, 1, 9Hz, 1H), 6.94 (dd,J=2, 7 Hz, 1H), 1.70 (dd,J=2, 7 Hz, 2H), 1.43 (dd,J=3,7 Hz, 2H). LC/MS (m/z)=350 (M+H)⁺.

To a 50 mL pressure vessel was added compound 6C (50 mg, 0.14 mmol),1,3-bis(diphenylphosphino)propane (11.8 mg, 0.03 mmol), palladium(II)acetate (6.4 mg, 0.03 mmol), 4 mL of methanol and triethylamine (0.06mL, 0.43 mmol). The vessel was sealed, bubbled with CO for 5 min, andthen pressurized to 25 PSI with CO. The reaction mixture was stirred at50° C. for 17 h under 25 PSI of CO. The mixture was cooled to roomtemperature, diluted with methanol, filtered through a pad of Celite andconcentrated in vacuo. The residue was partitioned between 20 mL ofEtOAc and 10 mL of brine. The organic layer was washed with (2×5 mL)water, dried over MgSO₄ and concentrated in vacuo to yield a residue.The residue was dissolved in acetonitrile, filtered and purified byreverse phase HPLC (Phen Luna 5u C18 column, 30 min gradient from20%-100% B. A=H₂O/CH₃CN/TFA 90:10:0.1. B=CH₃CN/H₂O/TFA 90:10:0.1), witha flow rate of 20 mL/min. The desired fractions were concentrated invacuo to yield compound 6D (32.2 mg, 68% yield) as a bright yellowsolid. ¹H NMR (methanol-d3): δ 7.75 (d,J=7 Hz, 1H), 7.54 (d,J=9 Hz, 1H),7.25-7.18(m,5H),3.96(s, 3H), 1.51 (dd,J=2, 7 Hz, 2H), 1.39(dd, J=3, 7Hz, 2H). LC/MS (m/z)=328 (M+H)⁺.

Example 6

To a solution of compound 6D (0.03 g, 0.09 mmol) in 2 mL of THF wasadded methylmagnesium chloride (0.09 mL, 0.28 mmol) dropwise over aperiod of 2 min, under nitrogen atmosphere. The reaction mixture wasstirred at room temperature for 1 h. After this time, the reactionmixture was quenched with 4 mL of saturated aqueous sodium chloride, theorganic layer was separated, and the aqueous layer was extracted (3×5mL) EtOAc. The combined organic layers were dried over MgSO₄ andconcentrated in vacuo to give the crude alcohol as an off-white solid.The solid was dissolved in methanol, filtered and purified by reversephase HPLC (Phen Luna 5u C18 column, 30 min gradient from 20%-100% B.A=H₂O/CH₃CN 90:10. B=CH₃CN/H₂0 90:10) with a flow rate of 30 mL/min. Thedesired fractions were concentrated in vacuo to yield Example 6 (17.2mg, 57% yield) as a white solid. ¹HNMR: δ 7.24-7.19 (m, 4H), 7.02-6.98(m, 2H), 6.80 (dd,J=2, 7 Hz, 1H), 1.75 (s, 6H), 1.60 (dd,J=3, 7 Hz, 2H),1.36 (dd,J=2, 7 Hz, 2H). The carbinol hydroxyl proton is not observed inthe ¹H NMR. LC/MS (m/z)=328/330 (M+H)⁺.

Examples 7 to 16

Examples 7 to 16 in Table 3 were synthesized according to the proceduresdescribed above, or by other similar methods known to one skilled in theart, with other appropriate reagents.

TABLE 3 LC/MS HPLC purity Example Structure (ES+, M + H) (%) 7

300 >95 8

340 >95 9

356 >95 10

362 >95 11

342 >95 12

296 >95 13

330 >95 14

370 >95 15

369 >95 16

382 >95

Example 172-(3-(4-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-ol

To a suspension of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylicacid (3.9 g, 18.2 mmol) in 60 mL of dichloromethane was addedN,N′-carbonyldiimidazole (4.4 g, 27.3 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 1 h, then4-fluoro-N′-hydroxybenzimidamide (5.0 g, 32.4 mmol) was added, followedby stirring at room temperature for 8 h. After this time, the mixturewas concentrated in vacuo, diluted in 40 mL of toluene and stirred atreflux for 16 h. After this time, the reaction mixture was cooled toroom temperature, diluted with 100 mL of ethyl acetate and washed with30 mL of brine. The organic layer was separated, dried over MgSO₄ andconcentrated in vacuo. The resulting crude material was purified byflash chromatography over 330 g of silica gel (elution with 0-20% ethylacetate in hexanes) to afford compound 17A (3.0 g, 9.1 mmol, 50%) as awhite solid. LCMS (m/z)=331 (M+H)⁺.

To a suspension of compound 17A (3.0 g, 9.1 mmol) in 7 mL of methanolwas added 4M aqueous LiOH (2.4 mL, 9.6 mmol) at room temperature. Uponcompletion of addition, the reaction mixture was stirred heated to 65°C. where it stirred for 3 h. At the conclusion of this period, thereaction mixture was cooled to room temperature and then concentrated invacuo. The resulting aqueous residue was partitioned between ethylacetate and water. The pH was adjusted to 1 by addition of concentrated.HCl. The organic layer was separated and the aqueous layer was extracted(3×15 mL) with ethyl acetate. The combined organic layers were driedover Na₂SO₄ and concentrated in vacuo to give compound 17B (2.8 g, 8.9mmol, 97%) as a white solid. LCMS (m/z)=315 (M−H)⁻.

To a solution of compound 17B (1.0 g, 3.2 mmol) in 25 mL of drytetrahydrofuran was added NMM (0.65 mL, 5.9 mmol) at room temperature.Upon completion of addition, the solution was cooled to 0° C. and ethylcarbonochloridate (0.38 mL, 3.95 mmol) was added dropwise. The resultingmixture was stirred at 0° C. for 30 min, and then3-bromo-2-hydrazinylpyridine (compound 1A, 1.49 g, 3.95 mmol) was addedin one portion. The reaction mixture was stirred at 0° C. for 30 min,and then at room temperature for 2.5 h. After this time, the reactionmixture was quenched with water. The organic layer was separated, driedover MgSO₄ and concentrated in vacuo. The resulting crude residue waspurified by flash chromatography over 120 g of silica gel (gradientelution with 0-40% ethyl acetate in hexanes) to give compound 17C (0.73g, 1.5 mmol, 47%) as a white solid. LCMS (m/z)=488 (M+H)⁺.

To a solution of compound 17C (0.73 g, 1.5 mmol) in 22 mL of a 2.7:1mixture of tetrahydrofuran and carbon tetrachloride, cooled to 0° C.,was added DIEA (2.1 mL, 12.0 mmol) followed by dropwise addition oftriethylphosphine (0.67 mL, 4.5 mmol). The resulting bright yellowsuspension was stirred at 0° C. for 1.5 h, at which point HPLC indicatedthat the starting material had been consumed. The reaction mixture wasthen quenched with water, and the organic layer was separated, driedover MgSO₄ and was concentrated in vacuo to yield the crude material.The crude material was taken up in 5 mL of methanol, and the resultingsolid was isolated by vacuum filtration and then washed with coldmethanol to yield compound 17D (0.48 g, 1.02 mmol, 68%) as a yellowsolid. LCMS (m/z)=470 (M+H)⁺.

To a pressure vessel was added compound 17D (0.4 g, 0.85 mmol), 17 mL ofmethanol, 1,3-bis(diphenylphosphino)propane (0.07 g, 0. 17 mmol),palladium(II) acetate (0.038 g, 0.17 mmol) and triethylamine (0.36 mL,2. 6 mmol). The pressure vessel was evacuated and then charged with 25PSI of CO at room temperature. The reaction mixture was then heated to60° C. where it stirred for 18 h. After this time, the reaction mixturewas cooled to room temperature. Once at the prescribed temperature, thereaction mixture was diluted with methanol, filtered through a pad ofCelite and concentrated in vacuo to yield a residue. The residue waspartitioned between 100 mL of ethyl acetate and 50 mL of brine. Theorganic layer was washed (2×25 mL) with water, dried over MgSO₄ andconcentrated in vacuo to yield the crude product. The crude product waspurified by flash chromatography over 40 g of silica gel (gradientelution with 0-100% ethyl acetate in hexanes) to provide compound 17E(0.35 g, 0.79 mmol, 93%) as a white solid. LCMS (m/z)=448 (M+H)⁺.

Example 17

To a solution of Compound 17E (100 mg, 0.22 mmol) in 4.5 mL oftetrahydrofuran was added dropwise a 3M THF solution of methylmagnesiumchloride (447 μL, 1.34 mmol) at room temperature. Upon completion ofaddition, the reaction mixture was stirred at room temperature for 2 h,and then an additional 6 eq of methylmagnesium chloride was added. After30 min, the reaction mixture was analyzed by HPLC, which showed that theketone had been consumed. The reaction mixture was then quenched with 10mL of saturated aqueous sodium chloride, 10 mL of saturated aqueousammonium chloride and then ethyl acetate was added until two clearphases emerged. The organic layer was separated and the aqueous layerwas extracted (3×10 mL) with ethyl acetate. The combined organic layerswere dried over MgSO₄ and concentrated in vacuo to yield the crudematerial. The crude material was purified by flash chromatography over40 g of silica gel (elution with 0-100% ethyl acetate in hexanes) toyield Example 17 (50 mg, 0.11 mmol, 50%) as a white solid. LCMS(m/z)=470 (M+H)⁺. LCMS (m/z)=448 (M+H)⁺.

Example 185-(4-(8-Cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)bicyclo[2.2.2]octan-1-yl)-3-(4-fluorophenyl)-1,2,4-oxadiazole

To a 10 mL microwave vial was added compound 17D (40 mg, 0.085 mmol),cyclopropylboronic acid (14.7 mg, 0. 17 mmol), potassium phosphate (54.4mg, 0.26 mmol), palladium (II) acetate (0.71 mg, 3.16 μmol),tricyclohexylphosphine (1.8 mg, 6.41 μmol), 739 μL toluene and 37 μL ofwater. Upon completion of addition, the vial was flushed with nitrogen,sealed and heated to 100° C. where it stirred for 18 h and then cooledto room temperature. Once at the prescribed temperature, the mixture wasdiluted with 5 mL of methanol, filtered through a pad of Celite andconcentrated in vacuo. The resulting residue was dissolved in 10 mL ofchloroform, washed with two 3 mL portions of water, dried over MgSO₄ andconcentrated in vacuo to yield a residue. This residue was dissolved inacetonitrile, filtered and purified by reverse phase HPLC (Phen AXIALuna 75×30 mm 5u column, 10 min gradient from 20-100% B. A=H₂O/CH₃CN/TFA90:10:0.1. B=CH₃CN/H₂O/TFA 90:10:0.1, with a flow rate of 30 mL/min).The desired fractions were collected and concentrated in vacuo withexcess sodium bicarbonate until the water remained. The aqueous layerwas extracted with chloroform, and the combined organic layers weredried over MgSO₄ and concentrated in vacuo to give Example 18 (20.0 mg,0.046 mmol, 53%) as a white solid. LCMS (m/z)=430 (M+H)⁺.

Example 192-(3-(1-(4-Chlorophenyl)cyclobutyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-amine,TFA Salt

To a solution of Example 14 (120 mg, 0.32 mmol) in dichloromethane (3.2mL) was added dropwise 1-chloro-N,N,2-trimethylprop-1-en-1-amine (52 μL,0.39 mmol) during a 1 minute period. Upon completion of addition thereaction mixture was stirred for 1 h and then it was concentrated invacuo. The resulting residue was dissolved in acetone (810 μL) and thena solution of sodium azide (32 mg, 0.49 mmol) in water (810 μL) wasadded dropwise during a 1 minute period. Upon completion of addition,the reaction mixture was stirred for 1 h. After this time, the reactionmixture was partitioned between diethyl ether and water and stirredvigorously for 15 minutes. At the conclusion of this period, the organicphase was separated, dried over sodium sulfate, and concentrated invacuo. The resulting residue was dissolved in toluene (3.24 mL) andheated to reflux where it stirred for 16 h. After this time, thereaction mixture was cooled to room temperature. Once at the prescribedtemperature, a solution of 4-methoxybenzyl alcohol (81 μL, 0.65 mmol) intoluene (300 μL) was added, and the resulting solution was heated toreflux where it stirred for 18 h. At the conclusion of this period, thereaction mixture was concentrated in vacuo and the resulting residue waspurified via flash chromatography (SiO₂, 0-100% ethyl acetate/hexanes)to afford compound 19A (115 mg, 71%) as a white foam. LC/MS (m/z)=505(M+H)⁺.

Example 19

To a solution of compound 19A (100 mg, 0.198 mmol) in dichloromethane(990 μL) was added trifluoroacetic acid (990 μL). Upon completion ofaddition the reaction mixture was stirred for 30 minutes and thencarefully poured in to excess 50% saturated aqueous sodium bicarbonate.The resulting mixture was stirred until all the acid was neutralized.The organic phase was separated, dried over sodium sulfate, andconcentrated in vacuo. The resulting residue was purified viapreparative HPLC (Phenomenex Axia Luna column (30×75 mm); 0-100% B over15 min, then 3 min B hold @ 40 mL/min; Solvent A=10% MeCN, 90% H₂O with0.1% TFA; Solvent B=90% MeCN, 10% H₂O with 0.1% TFA.) to provide Example19 (78.2 mg, 82%) as a white foam (TFA salt). LC/MS (m/z)=341 (M+H)⁺.HPLC Purity>95%.

Example 208-(2-(1H-Tetrazol-5-yl)propan-2-yl)-3-(1-(4-chlorophenyl)cyclobutyl)-[1,2,4]triazolo[4,3-a]pyridine

To a solution of Example 14 (102 mg, 0.276 mmol) in dichloromethane (2.8mL) was added dropwise 1-chloro-N,N,2-trimethylprop-1-en-1-amine (44 μL,0.331 mmol) during a 1 minute period. Upon completion of addition, thereaction mixture was stirred for 90 minutes. At the conclusion of thisperiod, the reaction mixture was cooled to 0° C. and then3-aminopropanenitrile (122 μL, 1.65 mmol) was added dropwise during a 1minute period. The resulting mixture was stirred for 30 minutes and thenthe cooling bath was removed. The mixture was stirred for 16 h and thenloaded onto a silica gel column and purified via flash chromatography(SiO₂, 0-30% [25% methanol/75% ethyl acetate]/hexanes, then re-purifiedon SiO₂ eluting with 0-100% ethyl acetate/hexanes) to afford compound20A (87 mg, 70%) as a colorless viscous oil. LC/MS (m/z)=422 (M+H)⁺.

To a solution of compound 20A (30 mg, 0.071 mmol) in dichloromethane(700 μL) was added pyridine (35 μL, 0.427 mmol), and phosphorouspentachloride (22 mg, 0. 107 mmol). The resulting mixture was heated toreflux where it stirred for 2h. After this time, the reaction mixturewas cooled to room temperature and azidotrimethylsilane (14 μL, 0.107mmol) was added. Upon completion of addition, the resulting mixture wasstirred for 16 h. At the conclusion of this period, moreazidotrimethylsilane (14 μL, 0.107 mmol) was added and the reactionmixture was stirred for an additional 2h. At the conclusion of thisperiod, the reaction mixture was loaded onto a silica gel column andpurified via flash chromatography (SiO₂, 0-60% ethyl acetate/hexanes) toprovide compound 20B (20 mg, 62%) as a colorless viscous oil. LC/MS(m/z)=447 (M+H)⁺.

Example 20

To a solution of compound 20B (16 mg, 0.36 mmol) in THF/MeOH (180 μL/180μL) was added aqueous sodium hydroxide (72 μL, 0.072 mmol, 1.0M). Theresulting mixture stirred vigorously for 16 h. After this time, the pHof the reaction mixture was adjusted to 3-4 with 1M aqueous HCl andresulting mixture was extracted with ethyl acetate. The combinedextracts were dried over sodium sulfate, and concentrated in vacuo. Theresulting residue was purified via flash chromatography (SiO₂, 0-60%[25% methanol/75% ethyl acetate]/hexanes) to furnish Example 20 (11 mg,77%) as a white solid. LC/MS (m/z)=394 (M+H)⁺.

Example 213-(1-(4-Bromophenyl)cyclopropyl)-8-(2-((2-(trimethylsilyl)ethoxy)methoxy)propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine

To a solution of methyl 2-chloronicotinate (10.0 g, 58.3 mmol) in THF(233 mL) was added a solution of methylmagnesium chloride (58.3 mL, 175mmol, 3.0M) during a 3 min period, which produced an exotherm to 50° C.Upon completion of addition, the reaction mixture was stirred for 30minutes. After this time, the reaction mixture was carefully quenchedwith 50% saturated aqueous ammonium chloride, and then partitionedbetween diethyl ether and excess 50% saturated aqueous ammoniumchloride. The resulting mixture was stirred vigorously for 30 minutes.The organic layer was separated, dried over sodium sulfate, andconcentrated in vacuo. The resulting oil was purified via flashchromatography (SiO₂, 0-100% ethyl acetate/hexanes) to afford compound21A (8.36 g, 84%) as a colorless viscous oil. LC/MS (m/z)=172 (M+H)⁺.

To a solution of compound 21A (4.0 g, 23.3 mmol), Hunig's base (16.3 mL,93.0 mmol), and tetrabutylammomiun iodide (18.9 g, 51.3 mmol) indichloromethane (46.6 mL) was added(2-(chloromethoxy)ethyl)trimethylsilane (8.2 mL, 46.6 mmol). Theresulting mixture was heated to reflux where it stirred for 22 h. At theconclusion of this period, the reaction mixture was loaded onto a silicagel column and purified via flash chromatography (SiO₂, 0-30% ethylacetate/hexanes) to provide compound 21B (5.34 g, 76%) as a colorlessoil. LC/MS (m/z)=302 (M+H)⁺.

To a solution of compound 21B (4.2 g, 13.9 mmol) in pyridine (13.5 mL)was added hydrazine (4.37 mL, 139 mmol). The resulting mixture washeated to 100° C. where it stirred for 5 days. After this time, thereaction mixture was concentrated in vacuo. The resulting oil waspurified via flash chromatography (SiO₂, 0-100% ethyl acetate/hexanes)to provide compound 21C (3.35 g, 81%) as a pale-yellow oil. LC/MS(m/z)=298 (M+H)⁺.

Example 21

To a 0° C. solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (810mg, 3.36 mmol) and N-methylmorpholine (407 μL, 3.70 mmol) in THF (13.5mL) was added dropwise isobutyl chloroformate (464 μL, 3.53 mmol) duringa 2 minute periods. Upon completion of addition, the mixture was stirredfor 2 h and then a solution of compound 21C (1.00 g, 3.36mmol) in THF(20 mL) was added during a 4 min period. Upon completion of addition,the reaction mixture was stirred for 1 h. After this time, the reactionmixture was partitioned between ethyl acetate and water. The organicphase was separated, dried over sodium sulfate, and concentrated invacuo. The resulting residue was dissolved in THF (20 mL) andcarbontetrachloride (13.5 mL) and then cooled to 0° C. Once at theprescribed temperature, Hunig's base (4.40 mL, 25.2 mmol) was added,followed by the dropwise addition of triethylphosphine (1.24 mL, 8.40mmol). The resulting mixture was stirred for 30 minutes and then anadditional triethylphosphine (600 μL) was added. Upon completion ofaddition, the reaction mixture was stirred for an additional 30 minutes.At the conclusion of this period, the reaction mixture was carefullyquenched with water, and then partitioned between ethyl acetate andwater. The organic phase was separated, dried over sodium sulfate, andconcentrated in vacuo. The resulting oil was purified via flashchromatography (SiO₂, 0-100% ethyl acetate/hexanes) to afford Example 21(1.16 g, 69%) as a pale-yellow viscous oil. LC/MS (m/z)=502 (M+H)⁺.

Example 222-(3-(1-(4-(1H-Tetrazol-5-yl)phenyl)cyclobutyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-ol

Compound 22A was prepared from Example 21 in a manner similar as theprocedure for compound 1D set forth above. LC/MS (m/z)=482 (M+H)⁺.

Compound 22B was prepared from compound 22A in a manner similar as theprocedure for compound 20A set forth above. LC/MS (m/z)=520 (M+H)⁺.

To a solution of compound 22B (82 mg, 0.158 mmol), triphenylphosphine(50 mg, 0. 190 mmol), and azidotrimethylsilane (25 μL, 0.190 mmol) in asolution of dichloromethane (1.6 mL) was added dropwisediethylazodicarboxylate (30 μL, 0.190 mmol) during a 1 minute period.Upon completion of addition, the mixture was stirred for 16 h. Afterthis time, additional triphenylphosphine (50 mg, 0.190 mmol),azidotrimethylsilane (25 μL, 0.190 mmol) and diethylazodicarboxylate (30μL, 0.190 mmol) were added. The reaction mixture was stirred for 2 h andthen loaded onto a silica gel column and purified via flashchromatography (SiO₂, 0-60% ethyl acetate/hexanes) to provide compound22C (53 mg, 61%) as a white foam. LC/MS (m/z)=545 (M+H)⁺.

To a 0° C. solution of compound 22C (50 mg, 0.092 mmol) indichloromethane (920 μL) was added trifluoroacetic acid (920 μL). Uponcompletion of addition, the reaction mixture was stirred for 1 h andthen carefully poured in to excess 50% saturated aqueous sodiumbicarbonate. The resulting mixture was stirred until all the acid wasneutralized. The organic phase was separated, dried over sodium sulfate,and concentrated in vacuo. The resulting residue was purified via flashchromatography (SiO₂, 0-100% [25% methanol/75% ethyl acetate]/hexanes)to furnish compound 22D (35 mg, 93%) as a white foam. LC/MS (m/z)=415(M+H)⁺.

Example 22

Example 22 was prepared from compound 22D in a manner similar to theprocedure for Example 20 set forth above. LC/MS (m/z)=362 (M+H)⁺. HPLCPurity=>99%.

Example 232-(3-(1-(1-Benzyl-1H-tetrazol-5-yl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-ol

Compound 23A was prepared in a manner similar to the procedure forExample 21 set forth above. LC/MS (m/z)=406 (M+H)⁺.

Compound 23B was prepared in a manner similar to the procedure forcompound 20A set forth above. LC/MS (m/z)=481 (M+H)⁺.

Compound 23C was prepared from compound 23B in a manner similar to theprocedure for compound 20B set forth above. LC/MS (m/z)=506 (M+H)⁺.

Example 23

Example 23 was prepared from compound 23C in a manner similar to theprocedure for Example 20 set forth above. LC/MS (m/z)=376 (M+H)⁺. HPLCPurity=>99%.

Example 242-(3-(1-(4-Phenylthiazol-2-yl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-ol

To a solution of1-(8-(2-(tert-butyldimethylsilyloxy)propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)cyclopropanecarboxamide(170 mg, 0.454 mmol) (prepared in a manner similar to the procedure forcompound 23B set forth above) in dichloromethane (2.3 mL) was a addedsolution of Lawesson's reagent (367 mg, 0.908 mmol) in dichloromethane(2.3 mL). Upon completion of addition, the mixture was stirred for 3days. After this time, more Lawesson's reagent (180 mg) was added andthe reaction mixture was stirred for an additional 24 h. At theconclusion of this period, the reaction mixture was carefully quenchedwith 25% saturated aqueous sodium bicarbonate, and then excess 25%saturated aqueous sodium bicarbonate and dichloromethane were added. Theresulting mixture was stirred vigorously for 30 min, which produced athick emulsion. After the emulsion had dissipated, the organic layer wasseparated, dried over brine and then sodium sulfate, and thenconcentrated in vacuo. The resulting residue was purified via flashchromatography (SiO₂, 0-30% [25% methanol/75% ethyl acetate]/hexanes) toafford compound 24A (142 mg, 80%) as a pale-yellow solid. LC/MS(m/z)=391 (M+H)⁺.

Example 24

To a solution of compound 24A (20 mg, 0.051 mmol) in THF (510 μL) wasadded 2-bromo-1-phenylethanone (20 mg, 0.102 mmol). Upon completion ofaddition, the reaction mixture was stirred for 16 h. At the conclusionof this period, the reaction mixture was partitioned between ethylacetate and 50% saturated aqueous sodium bicarbonate. The resultingmixture stirred vigorously for 15 min. The organic layer was separated,dried over sodium sulfate, and then concentrated in vacuo. The resultingresidue was dissolved in THF (510 μL), and a solution oftetrabutylammonium fluoride (153 μL, 0.153 mmol, 1.0M) was added. Uponcompletion of addition, the resulting mixture was heated to reflux whereit stirred for 1 h. After this time, the reaction mixture was cooled toroom temperature and then partitioned between ethyl acetate and 50%saturated aqueous ammonium chloride. The resulting mixture was stirredvigorously for 15 min. The organic layer was separated, dried over brineand then sodium sulfate, and concentrated in vacuo. The resultingresidue was purified via flash chromatography (SiO₂, 0-60% [25%methanol/75% ethyl acetate]/hexanes) to afford Example 24 (4.9 mg, 25%)as a an off-white foam. LC/MS (m/z)=377 (M+H)⁺. HPLC Purity>99%.

Examples 25 to 119

Examples 25 to 119 in Table 4 were synthesized according to theprocedures described above, or by other similar methods known to oneskilled in the art, with other appropriate reagents.

TABLE 4 LC/MS HPLC purity Example Structure (ES+, M + H) (%) 25

358 >95 26

358 >95 27

376 >95 28

356 >95 29

360 >95 30

378 >95 31

383 >95 32

413 >95 33

397 >95 34

362 >95 35

505 >95 36

419 >95 37

383 >95 38

399 >95 39

312 >95 40

352 >95 41

308 >95 42

410 >95 43

324 >95 44

310 >95 45

338 >95 46

294 >95 47

334 >95 48

322 >95 49

336 >95 50

350 >95 51

388 >95 52

372 >95 53

352 >95 54

346 >95 55

324 >95 56

338 >95 57

422 >95 58

430 >95 59

447 >95 60

370 >95 61

420 >95 62

416 >95 63

390 >95 64

415 >95 65

356 >95 66

406 >95 67

390 >95 68

396 >95 69

353 >95 70

370 >95 71

370 >95 72

356 >95 73

396 >95 74

353 >95 75

394 >95 76

369 >95 77

418 >95 78

404 >95 79

442 >95 80

262 >95 81

314 >95 82

342 >95 83

371 >95 84

372 >95 85

351 >95 86

365 >95 87

377 >95 88

407 >95 89

393 >95 90

386 >95 91

389 >95 92

330 >95 93

391 >95 94

405 >95 95

389 >95 96

373 >95 97

314 >95 98

314 >95 99

367 >95 100

423 >95 101

375 >95 102

377 >95 103

362 >95 104

360 >95 105

374 >95 106

324 >95 107

310 >95 108

380 >95 109

395 >95 110

394 >95 111

411 >95 112

376 >95 113

363 >95 114

446 >95 115

410 >95 116

361 >95 117

376 >95 118

218 >95 119

316 >95

Assay(s) for 11-Beta-Hydroxysteroid Dehydrogenase Activity

The in vitro inhibition of recombinant human 11beta-HSD1 was determinedas follows.

[³H]-Cortisone with a specific radioactivity of 50 Ci/mmol (ART 743,Lot: 050906) was from American Radiolabeled Chemicals, Inc. (St Louis,Mo.); monoclonal ab to Cortisol (P01-9294M-P, Lot: L-28) was from EastCoast Bio., (North Berwick, Me.); Protein A-yttrium silicate, type-1,SPA bead NJ® (RPN-143) was from Amersham LifeSciences, (Piscataway,N.J.); 384 well-Optiplate384® (#6007299) was from PerkinElmer (Boston,Mass.); DPBS, pH 7.4 (14040) is from GIBCO, (Grand Island, N.Y.);carbenoxolone (C4790) is from Sigma, (St Louis, Mo.).

Full length recombinant human 11β-HSD1 cDNAs and the cDNA encoding human11β-HSD2 were expressed stably in HEK 293 EBNA cells. Cells were grownin DMEM (high glucose) containing MEM non-essential amino acids,L-glutamine, hygromycin B (200 μg/ml), and G-418(200 μg/ml) in thepresence of 10% FBS.

Human 11β-HSD1 transfected HEK 293 EBNA cells were grown to 80%confluency and the cell pellet was quick frozen and stored at −80° C.before purification. Cell paste, 40 g from −80° C. storage, was thawedin water and then 100 ml of homogenization buffer H (0.01 M sodiumphosphate pH 6.5 containing 0.25 M sucrose and protease inhibitorcocktail (Roche #1836145 1 tablet per 50 ml) were added to completelythaw the paste. The cell paste suspension was homogenized using aPolytron for 20 seconds to create a homogeneous mixture. Additionalbuffer H was added to a volume of 300 ml and cells were broken openusing a N2-bomb (at 4° C.) in two batches by treating at 500 psi. Theextract was centrifuged at 750×g for 30 min. The supernatant wascentrifuged at 20,000×g for 30 min. The supernatant was furthercentrifuged at 105,000×g for 60 min. The 105,000×g pellet wasresuspended in buffer H and centrifuged at 105,000×g for 60 min. Themicrosome pellet was scraped from the bottom of tube and resuspended in0.01M phosphate buffer, pH 6.5 containing protease inhibitors (Roche#1836145, 1 tablet per 50 ml). Aliquots were stored at −80° C. untilneeded. The protein concentration was measured by the BioRad methodusing BSA standard.

Compounds were dissolved in DMSO to obtain 10 mM stock concentrations.From the 10 mM stock, the compounds were diluted in DMSO to achieve theconcentrations.

11β-HSD1 SPA Enzyme Assay

11β-HSD1 was assayed by Scintillation Proximity assay in a 384-wellPerkin Elmer white plate. The dose response of the compounds wasdetermined using 11 half-log dilutions of compound in DMSO in duplicate.To each well, 0.5 μl of compound dilution in DMSO were added. 15 μl ofassay buffer (for blanks) or 15 μl of human microsomes in assay bufferwere added next and the plates were incubated for 10 min at roomtemperature. The final microsomal protein concentration was 1.1μg/assay. Duplicates were in the same plate one row below the other. 10μl of ³H-cortisone (final concentration 40 nM) was added to each welland the plate was spun down to mix and bring down the contents to thebottom of the wells. The plates were incubated at room temperature withgentle shaking for 4 hrs. The reaction was stopped with addition of 10μl of 10 mM carbenoxolone. Then, 0.5 mg of yttrium silicate SPA beadscoupled to anti-cortisol antibody in 20 μl were added to all the wellsof plate, which were spun down once more and incubated at roomtemperature overnight. The plate was read in a TopCount® (1 min/well).Data were uploaded automatically to Tool Set, a Lead Evaluationinformatics program for data capture and calculation. Graphs weregenerated with the Curve Master program.

Compounds of the present invention were tested in the assay describedimmediately above and the results shown in the Table 5 below wereobtained.

TABLE 5 h HSD1 Example IC₅₀ (nM) 1 2.3 6 20 42 72 51 0.4 54 0.7 59 549572 0.5 80 7703 86 35 90 1382 104 191 109 0.6 110 104 111 0.5 112 2822

The in vivo inhibition of recombinant human 11beta-HSD1 was determinedas follows.

Studies were conducted utilizing diet induced obese (DIO) mice obtainedfrom Jackson Laboratory (ME, USA). These mice were fed a 60% fat diet(Research Diets D12492) soon after weaning and kept on this diet for 24weeks. These mice were individually housed. All mice were housed undercontrolled temperature (23° C.) and lighting (12 hours of light between6 am to 6 pm, 12 hours of dark) with free access to water. The animalscontinued on this diet and were utilized for experimentation at 30 to 32weeks of age, at which time these mice weighed 45 to 55 grams.

The basic model of 11-dehydrocorticosterone (DHC) administration to miceto produce corticosterone has been reported in the literature forclinical and preclinical evaluation of the activity of 11β-HSD.Essentially DHC (Steraloids Inc., Newport R.I.), was suspended in thevehicle at a concentration of 10 mg/kg in a volume of 7.5 ml/kg of mousebody weight. For a typical study, non-fasting mice were weighed andseparated into groups (n=6) where body weights are not statisticallydifferent from each other. Animals were bled via a tail knick, for a 0time sample and then dosed orally (7.5 ml/kg) with vehicle or drug. At60 minutes post administration of vehicle or compound, mice were bledagain via the tail tip and dosed orally (7.5 ml/kg) with DHC 10 mg/kg.All animals were subsequently bled at 30, 60 and 120 minutes post DHCdosing. Thirty-five microliters of whole blood are collected per timepoint in microvette tubes coated with EDTA (Sarstedt Tubes Microvette CB300/Haematology Potassium EDTA #16.444.300) and kept on ice. Sampleswere centrifuged at 4° C. in a Beckman Coulter centrifuge for 10 minutesat 2500 RPM. Plasma was separated and collected and immediately frozenat −20° C. until corticosterone analysis could be assessed.

Plasma Corticosterone was measured using an EIA (IDS AC-14F1). Sampleswere measured at (1:2) for the −30(or −60 minute) and 0 time point and(1:10) for the 30, 60 and 120 minutes time points. AUC was calculatedusing Graphpad and the zero timepoint was used as the baseline. One wayANOVA was calculated using Sigmastat. A p value of less that 0.05 viapost hoc analysis with Dunnett's was used to determine statisticalsignificance.

The vehicle utilized for the suspension of the compounds was 0.5%methocel; 0.1% tween 80 in water. Methocel Cellulose (M-0262) waspurchased from Sigma-Aldrich, St Louis, Mo. 6. Tween 80 (274364) waspurchased from Sigma-Aldrich, St Louis, Mo. Compounds were administeredin 7.5 ml/kg volumes at final dosages of 0.1 to 300 mg/kg depending onthe study and compound evaluated.

Compound(s) of the present invention were tested in the assay describedimmediately above and the results shown in the Table 6 below wereobtained.

TABLE 6 Example Dose % inhibition 1 30 mpk 53 11 30 mpk 69

Utilities and Combinations

A. Utilities

The compounds of the present invention possess activity as inhibitors ofthe enzyme 11-beta-hydroxysteroid dehydrogenase type I, and, therefore,may be used in the treatment of diseases associated with11-beta-hydroxysteroid dehydrogenase type I activity. Via the inhibitionof 11-beta-hydroxysteroid dehydrogenase type I, the compounds of thepresent invention may preferably be employed to inhibit or modulateglucocorticoid production, thereby interrupting or modulating cortisoneor cortisol production.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating,preventing, or slowing the progression of diabetes and relatedconditions, microvascular complications associated with diabetes,macrovascular complications associated with diabetes, cardiovasculardiseases, Metabolic Syndrome and its component conditions, inflammatorydiseases and other maladies. Consequently, it is believed that thecompounds of the present invention may be used in preventing,inhibiting, or treating diabetes, hyperglycemia, impaired glucosetolerance, insulin resistance, hyperinsulinemia, retinopathy,neuropathy, nephropathy, delayed wound healing, atherosclerosis and itssequelae (acute coronary syndrome, myocardial infarction, anginapectoris, peripheral vascular disease, intermittent claudication),abnormal heart function, myocardial ischemia, stroke, MetabolicSyndrome, hypertension, obesity, dislipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL,non-cardiac ischemia, infection, cancer, vascular restenosis,pancreatitis, neurodegenerative disease, lipid disorders, cognitiveimpairment and dementia, bone disease, HIV protease associatedlipodystrophy, glaucoma and inflammatory diseases, such as, rheumatoidarthritis, Cushing's Disease, Alzheimer's Disease and osteoarthritis.

Metabolic Syndrome or “Syndrome X” is described in Ford et al., J. Am.Med. Assoc., 287:356-359 (2002) and Arbeeny et al., Curr. Med.Chem.-Imm., Endoc. & Metab. Agents, 1: 1-24 (2001).

B. Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s), e.g., an antidiabetic agent or otherpharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other 11-beta-hydroxysteroid dehydrogenase type I inhibitors or oneor more other suitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dislipidemic agents,anti-dyslipidemic agents, anti-hyperlipidemic agents,anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents,anti-restenotic agents, anti-pancreatic agents, lipid lowering agents,appetite suppressants, memory enhancing agents, cognition promotingagents and anti-inflammatory agents.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include insulin and insulinanalogs: LysPro insulin, inhaled formulations comprising insulin;glucagon-like peptides; sulfonylureas and analogs: chlorpropamide,glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide,glyburide, glimepiride, repaglinide, meglitinide; biguanides: metformin,phenformin, buformin; alpha2-antagonists and imidazolines: midaglizole,isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulinsecretagogues: linogliride, insulinotropin, exendin-4, BTS-67582,A-4166; thiazolidinediones: ciglitazone, pioglitazone, troglitazone,rosiglitazone; PPAR-gamma agonists; PPAR-alpha agonists; PPARalpha/gamma dual agonists; SGLT2 inhibitors; dipeptidyl peptidase-IV(DPP4) inhibitors; glucagon-like peptide-1 (GLP-1) receptor agonists;aldose reductase inhibitors; RXR agonists: JTT-501, MCC-555, MX-6054,DRF2593, GI-262570, KRP-297, LG100268; fatty acid oxidation inhibitors:clomoxir, etomoxir; α-glucosidase inhibitors: precose, acarbose,miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945;beta-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243,TAK-667, AZ40140; phosphodiesterase inhibitors, both cAMP and cGMP type:sildenafil, L686398: L-386,398; amylin antagonists: pramlintide, AC-137;lipoxygenase inhibitors: masoprocal; somatostatin analogs: BM-23014,seglitide, octreotide; glucagon antagonists: BAY 276-9955; insulinsignaling agonists, insulin mimetics, PTP1B inhibitors: L-783281,TER17411, TER17529; gluconeogenesis inhibitors: GP3034; somatostatinanalogs and antagonists; antilipolytic agents: nicotinic acid, acipimox,WAG 994; glucose transport stimulating agents: BM-130795; glucosesynthase kinase inhibitors: lithium chloride, CT98014, CT98023; andgalanin receptor agonists.

Other suitable thiazolidinediones include Mitsubishi's MCC-555(disclosed in U.S. Pat. No. 5,594,016), Glaxo-Wellcome's GL-262570,englitazone (CP-68722, Pfizer), or darglitazone (CP-86325, Pfizer,isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702(Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi).

Suitable PPAR alpha/gamma dual agonists include AR-HO39242(Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck), aswell as those disclosed by Murakami et al., “A Novel Insulin SensitizerActs As a Coligand for Peroxisome Proliferation—Activated Receptor Alpha(PPAR alpha) and PPAR gamma; Effect of PPAR alpha Activation on AbnormalLipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes, 47:1841-1847(1998), and WO 01/21602, the disclosure of which is incorporated hereinby reference, employing dosages as set out therein, which compoundsdesignated as preferred are preferred for use herein.

Suitable alpha2 antagonists also include those disclosed in WO 00/59506,employing dosages as set out herein.

Suitable SGLT2 inhibitors include T-1095, phlorizin, WAY-123783, andthose described in WO 01/27128.

Suitable DPP4 inhibitors include saxagliptan, sitagliptan, vildagliptin,and denagliptan.

Suitable aldose reductase inhibitors include those disclosed in WO99/26659.

Suitable meglitinides include nateglinide (Novartis) or KAD1229(PF/Kissei).

Examples of glucagon-like peptide-1 (GLP-1) receptor agonists includeExenatide (Byetta™), NN2211 (Liraglutide, Novo Nordisk), AVE0010(Sanofi-Aventis), R1583 (Roche/Ipsen), SUN E7001 (Daiichi/Santory),GSK-716155 (GSK/Human Genome Sciences) and Exendin-4 (PC-DAC™).

Other anti-diabetic agents that can be used in combination withcompounds of the invention include ergoset and D-chiroinositol.

Suitable anti-ischemic agents include, but are not limited to, thosedescribed in the Physicians' Desk Reference and NHE inhibitors,including those disclosed in WO 99/43663.

Examples of suitable lipid lowering agents for use in combination withthe compounds of the present invention include one or more MTPinhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, cholesterol ester transfer protein inhibitors (e.g.,CP-529414 (Pfizer)), and/or nicotinic acid and derivatives thereof.

MTP inhibitors which may be employed as described above include thosedisclosed in U.S. Pat. Nos. 5,595,872, 5,739,135, 5,712,279, 5,760,246,5,827,875, 5,885,983 and 5,962,440.

The HMG CoA reductase inhibitors which may be employed in combinationwith one or more compounds of formula I include mevastatin and relatedcompounds, as disclosed in U.S. Pat. No. 3,983,140, lovastatin,(mevinolin) and related compounds, as disclosed in U.S. Pat. No.4,231,938, pravastatin, and related compounds, such as disclosed in U.S.Pat. No. 4,346,227, simvastatin, and related compounds, as disclosed inU.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductaseinhibitors which may be employed herein include, but are not limited to,fluvastatin, disclosed in U.S. Pat. No. 5,354,772; cerivastatin, asdisclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080; atorvastatin, asdisclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and5,686,104; atavastatin (Nissan/Sankyo's nisvastatin (NK-104)), asdisclosed in U.S. Pat. No. 5,011,930; visastatin (Shionogi-Astra/Zeneca(ZD-4522)) as disclosed in U.S. Pat. No. 5,260,440.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, atavastatin, and ZD-4522.

The fibric acid derivatives which may be employed in combination withone or more compounds of formula I include fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate, and the like,probucol, and related compounds, as disclosed in U.S. Pat. No.3,674,836, fenofibrate and gemfibrozil being preferred, bile acidsequestrants, such as cholestyramine, colestipol and DEAE-Sephadex(Secholex , Policexide ), as well as lipostabil (Rhone-Poulenc), EisaiE-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402),tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58-035, American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives, such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes, such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

The ACAT inhibitor which may be employed in combination with one or morecompounds of formula I include those disclosed in Drugs of the Future,24:9-15 (1999) (Avasimibe); Nicolosi et al., “The ACAT inhibitor,Cl-1011 is effective in the prevention and regression of aortic fattystreak area in hamsters”, Atherosclerosis (Shannon, Irel.), 137(1):77-85(1998); Ghiselli, G., “The pharmacological profile of FCE 27677: a novelACAT inhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB100-containing lipoprotein”,Cardiovasc. Drug Rev., 16(1):16-30 (1998); Smith, C. et al., “RP 73163:a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”, Bioorg.Med. Chem. Lett., 6(1):47-50 (1996); Krause, B. R. et al., Chapter 6:“ACAT Inhibitors: Physiologic Mechanisms for Hypolipidemic andAnti-Atherosclerotic Activities in Experimental Animals”, Inflammation:Mediators and Pathways, CRC Press, Inc., publ., Ruffolo, Jr., R. R. etal., eds., pp. 173-198 (1995); Sliskovic et al., “ACAT inhibitors:potential anti-atherosclerotic agents”, Curr. Med. Chem., 1(3):204-25(1994); Stout et al., “Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents. 6. The firstwater-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of aseries of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureaswith enhanced hypocholesterolemic activity”, Chemtracts: Org. Chem.,8(6):359-362 (1995), or TS-962 (Taisho Pharmaceutical Co. Ltd.).

The hypolipidemic agent may be an upregulator of LDL receptor activity,such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

Examples of suitable cholesterol absorption inhibitors for use incombination with the compounds of the invention include ezetimibe(Zetia®).

Examples of suitable ileal Na⁺/bile acid cotransporter inhibitors foruse in combination with the compounds of the invention include compoundsas disclosed in Drugs of the Future, 24:425-430 (1999).

The lipoxygenase inhibitors which may be employed in combination withone or more compounds of formula I include 15-lipoxygenase (15-LO)inhibitors, such as benzimidazole derivatives, as disclosed in WO97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones,as disclosed in WO 96/38144, and 15-LO inhibitors, as disclosed bySendobry et al., “Attenuation of diet-induced atherosclerosis in rabbitswith a highly selective 15-lipoxygenase inhibitor lacking significantantioxidant properties”, Brit. J. Pharmacology, 120:1199-1206 (1997),and Cornicelli et al., “15-Lipoxygenase and its Inhibition: A NovelTherapeutic Target for Vascular Disease”, Current Pharmaceutical Design,5:11-20 (1999).

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include beta adrenergicblockers, calcium channel blockers (L-type and T-type; e.g., diltiazem,verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g.,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), renin inhibitors (e.g., aliskiren), ACE inhibitors(e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril,cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1receptor antagonists (e.g., losartan, irbesartan, valsartan), ETreceptor antagonists (e.g., sitaxsentan, atrsentan, and compoundsdisclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AIIantagonist (e.g., compounds disclosed in WO 00/01389), neutralendopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include a cannabinoid receptor 1antagonist or inverse agonist, a beta 3 adrenergic agonist, a lipaseinhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroidreceptor beta drug, and/or an anorectic agent.

Cannabinoid receptor 1 antagonists and inverse agonists which may beoptionally employed in combination with compounds of the presentinvention include rimonabant, SLV 319, CP-945598 (Pfizer), SR-147778(Sanofi-Aventis), MK0364 (Merck) and those discussed in Hertzog, D. L.,Expert Opin. Ther. Patents, 14:1435-1452 (2004).

The beta 3 adrenergic agonists which may be optionally employed incombination with compounds of the present invention include AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer), or otherknown beta 3 agonists, as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983, and 5,488,064, with AJ9677, L750,355,and CP331648 being preferred.

Examples of lipase inhibitors which may be optionally employed incombination with compounds of the present invention include orlistat orATL-962 (Alizyme), with orlistat being preferred.

The serotonin (and dopamine) reuptake inhibitor and/or modulator whichmay be optionally employed in combination with a compound of formula Imay be sibutramine, topiramate (Johnson & Johnson), APD-356 (Arena) oraxokine (Regeneron), with sibutramine and APD-356 being preferred.

Examples of thyroid receptor beta compounds which may be optionallyemployed in combination with compounds of the present invention includethyroid receptor ligands, such as those disclosed in WO 97/21993 (U. CalSF), WO 99/00353 (KaroBio), and WO 00/039077 (KaroBio), with compoundsof the KaroBio applications being preferred.

The anorectic agent which may be optionally employed in combination withcompounds of the present invention include dexamphetamine, phentermine,phenylpropanolamine, or mazindol, with dexamphetamine being preferred.

Other compounds that can be used in combination with the compounds ofthe present invention include CCK receptor agonists (e.g., SR-27895B);MCHR₁ antagonist (e.g., GSK 856464); galanin receptor antagonists; MCR-4antagonists (e.g., HP-228); leptin or mimetics; urocortin mimetics, CRFantagonists, and CRF binding proteins (e.g., RU-486, urocortin).

Further, the compounds of the present invention may be used incombination with HIV protease inhibitors, including but not limited toReyataz® and Kaletra®.

Examples of suitable memory enhancing agents, anti-dementia agents, orcognition promoting agents for use in combination with the compounds ofthe present invention include, but are not limited to, donepezil,rivastigmine, galantamine, memantine, tacrine, metrifonate, muscarine,xanomelline, deprenyl and physostigmine.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include, but are not limitedto, prednisone, acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha,prednisolone, methylprednisolone, dexamethazone, flucatisone,betamethasone, hydrocortisone and beclomethasone.

The aforementioned patents and patent applications are incorporatedherein by reference.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

The compounds of formula I can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intrastemal injection, or infusion techniques (e.g.,as sterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents.

In carrying out the method of the invention for treating diabetes andrelated diseases, a pharmaceutical composition will be employedcontaining the compounds of formula I, with or without otherantidiabetic agent(s) and/or antihyperlipidemic agent(s) and/or othertype therapeutic agents in association with a pharmaceutical vehicle ordiluent. The pharmaceutical composition can be formulated employingconventional solid or liquid vehicles or diluents and pharmaceuticaladditives of a type appropriate to the mode of desired administration,such as pharmaceutically acceptable carriers, excipients, binders, andthe like. The compounds can be administered to a mammalian patient,including humans, monkeys, dogs, etc. by an oral route, for example, inthe form of tablets, capsules, beads, granules or powders. The dose foradults is preferably between 1 and 2,000 mg per day, which can beadministered in a single dose or in the form of individual doses from1-4 times per day.

A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg), and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of compounds of structure I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

What is claimed is:
 1. A compound, enantiomers, diastereomers, or saltsthereof, selected from the group consisting of:


2. A compound, enantiomers, diastereomers, or salts thereof, that is


3. A compound, enantiomers, diastereomers, or salts thereof, that is


4. A compound, enantiomers, diastereomers, or salts thereof, that is


5. A compound, enantiomers, diastereomers, or salts thereof, that is


6. The compound of claim 2, wherein the compound is the hydrochloride orbisulfate salt.
 7. The compound of claim 6 that is a crystalline form ofsaid hydrochloride or bisulfate salt.
 8. A pharmaceutical compositioncomprising a compound of claim
 1. 9. The pharmaceutical composition ofclaim 8 further comprising a pharmaceutically acceptable carrier, andoptionally at least one additional therapeutic agent.
 10. A process forpreparing a compound having the formula (VII-f)

comprising reacting a hydrazide of formula VII-d with a carboxylic acidor Ph₃PCl₂/diisopropyl ethylamine in the presence of a solvent atelevated temperature to afford a 1,2,4-triazolopyridine of formula VII-eand then contacting the 1,2,4-triazolopyridine of formula VII-e with anappropriate acid to provide the compound of formula (VII-f):


11. The process of claim 10, wherein the hydrazide of formula VII-d

is prepared by reacting a hydrazinylpyridinyl hydrochloride of formulaVII-b with an acid of formula VII-c and oxalyl chloride in a solvent inthe presence of a base:


12. The process of claim 11, wherein the hydrazinylpyridinylhydrochloride of formula VII-b

is prepared by first reacting a halopyridine of formula VII-a with ahydrazine at an elevated temperature followed by HCl salt formation withhydrochloric acid to form the hydrazinylpyridinyl hydrochloride offormula VII-b:


13. A pharmaceutical composition comprising a compound of claim
 2. 14.The pharmaceutical composition of claim 13 further comprising apharmaceutically acceptable carrier, and optionally at least oneadditional therapeutic agent.
 15. A pharmaceutical compositioncomprising a compound of claim
 3. 16. The pharmaceutical composition ofclaim 15 further comprising a pharmaceutically acceptable carrier, andoptionally at least one additional therapeutic agent.
 17. Apharmaceutical composition comprising a compound of claim
 4. 18. Thepharmaceutical composition of claim 17 further comprising apharmaceutically acceptable carrier, and optionally at least oneadditional therapeutic agent.
 19. A pharmaceutical compositioncomprising a compound of claim
 5. 20. The pharmaceutical composition ofclaim 19 farther comprising a pharmaceutically acceptable carrier, andoptionally at least one additional therapeutic agent.